Immunology (1955-1975): The Natural Selection Theory, the Two Signal Hypothesis and Positive Repertoire Selection

DONALD R. FORSDYKE   Journal of the History of Biology (2012) 45, 139-161

 Submitted  28th October 2010.  Accepted 30th January 2011  The final published version, closely resembling this version, is available by way of SpringerLink Click Here.













End_Note_June_2011 Eichman's Network Collective

End_Note_Jan_2012 MHC as Blank Slate Scenario

End_Note_Feb_2013 Mel backs off

End_Note_Mar_2013 Absense-of-Knowledge Postulate










Observations suggesting the existence of natural antibody prior to exposure of an organism to the corresponding antigen, led to the natural selection theory of antibody formation of Jerne in 1955, and to the two signal hypothesis of Forsdyke in 1968. Aspects of these were not only first discoveries but also foundational discoveries in that they influenced contemporaries in a manner that, from our present vantage point, appears to have been constructive. Jerne's later hypothesis (1971), that antibody-like receptors on lymphocytes were selected over evolutionary time for reactivity with the major histocompatibility complex (MHC) antigens of the species, was a first, but it was incorrect, and was foundational only to the extent that it emphasized the need to explain the Simonsen phenomenon. Although easily construed as derivative of Jerne (1971), the affinity/avidity model of Forsdyke (1975), which predicted that cell-surface components, including MHC antigens, would restrict antigen-reactivity by somatically shaping lymphocyte repertoires, was actually an extension of the two signal hypothesis. While presenting a mechanism for the positive selection of lymphocyte repertoires, and explaining the Simonsen phenomenon, the affinity/avidity model was not foundational in that it had to be independently rediscovered. For science to advance optimally we must seek to close temporal gaps so that first discoveries are also foundational. Listening to young scientists may be part of the solution.


Keywords: Affinity/avidity model, Ehrlich's dilemma, Niels Jerne, major histocompatibility complex, positive repertoire selection, Simonsen phenomenon


The clonal selection theory transformed immunology (Burnet 1959; Forsdyke 1995a).1 Analysis of this paradigm shift, comparable to the emergence of Mendelism a half century earlier, is an on-going task (Soderqvist and Stillwell 1999). As with Mendelism (Barber 1961; Cock and Forsdyke 2008), the transition involved colorful figures and spirited defenses of old ways. Much of the transformation occurred in the decade that began with the natural selection theory of Jerne (1955). In the following decade clonal selection was consolidated and extended. The extensions included the two signal hypothesis and the affinity/avidity model for the shaping of lymphocyte repertoires.

     In a deeply perceptive biography, Soderqvist (2003) related the various roles of Niels Jerne in these 'decades of major and radical transition in the field' (Soderqvist and Stillwell 1999). As a laboratory scientist and theoretician, I was, in a small way, also a participant in the transition. Thus, I am able to contribute elements to the story that may be of historical interest. Apart from providing primary source material, the present paper draws attention to problems of the young theoretician, and the need to close the gap between first discoveries and discoveries later deemed to have been foundational in the sense that they have positively contributed to scientific advance.

Natural Antibody

Historians have suggested that the first two signal hypothesis was that which I presented in 1968 (Podolsky and Tauber 1997, p. 152; Doherty and Robertson 2004). There is a parallel between the genesis of this hypothesis and the earlier genesis of the natural selection theory of antibody formation (Jerne 1955); both were inspired by the idea of 'natural antibody.' There is also a link with later emerging ideas on the shaping of lymphocyte repertoires prior to an organism's encounter with foreign antigens (Jerne 1971).2

    The natural selection theory came to the 42 year old Niels Jerne while walking near the Knippel Bridge in Copenhagen in the summer of 1954 (Soderqvist 2003, p. 247). By this date he was an established figure in his field - a man of considerable savoir faire with friends who could smooth the path to publication, achieved in November 1955. On the other hand, the two signal hypothesis came one spring day in 1966 to a 27 year old, relatively naive, doctoral student in Cambridge, England. Jerne later gave an account of the genesis of his theory (Jerne 1966); but Soderqvist (1994), from a study of Jerne's archived papers, concluded that his autobiographical story 'is not satisfactory as a source document for the reconstruction of conceptual origins.' The same caveat may apply to the story the Cambridge student will here relate. And it should also be noted that others were thinking along two signal lines. For example, in the USA Herman Eisen (1966), referring to bivalent cell surface receptors as 'sentinel' antibodies, wrote: 'If 1 of the sentinel antibody's 2 sites is occupied by the antigenic determinant, the cell is stimulated - - . But if both of the sentinel's sites are occupied, the cell is not stimulated - i.e. it is suppressed or remains dormant.'3

    For both Jerne and myself, ideas were triggered by experimental observations relating to 'natural antibody' - antibody present in an organism prior to that organism's exposure to the specific antigen to which the antibody could bind. When studying the reactivity of viruses with blood serum in the spring of 1954, Jerne unexpectedly discovered an activity - dubbed 'P-star' - which he interpreted as due to natural antibody. This set off a train of thought leading to a theory of antibody formation that seemed to unify disparate observations better than some alternatives (Jerne 1955). He postulated a process by which an organism would, somehow, randomly generate a repertoire of antibodies covering a wide range of specificities. An incoming antigen (e.g. virus) would select the antibody that best complemented it, and would then conduct it to a cell where the antibody would, somehow, be replicated and secreted in large quantities (thus increasing protection against the virus). At the time of their first 'natural' generation, antibodies that reacted with 'self' antigens would have been absorbed by 'structures in the body of the animal itself' so that auto-immune reactivity would not develop.

    In the decade that followed there were many outstanding discoveries that reoriented immunology within a clonal selection framework. From a state of relative impoverishment, immunological knowledge suddenly expanded. The randomization process postulated by Jerne would first generate a repertoire, not of antibodies, but of lymphocytes bearing antibody-like receptors. Each lymphocyte, on being selected by specific antigen by virtue of its complementary receptor, would clonally expand and secrete large quantities of the corresponding antibody. It was found that antibodies had constant and variable regions (Porter 1958), which implied that constancy and variability could be aspects of the corresponding DNA sequences (Brenner and Milstein 1966). There were central lymphoid organs, such as the thymus, where immunological competence was conferred on naive stem cells (Miller 1961). The small lymphocytes emerging from such 'factories' were long-lived and, assisted by their smallness, were able to circulate around the body, like police ready to spring into action should an intruder appear (Gowans and Uhr 1966). When cultured in a synthetic medium containing blood serum, 'resting' small lymphocytes could be artificially activated by lectins (plant proteins that bound to cell surfaces). The lymphocytes then enlarged and proliferated, displaying features similar to those seen within peripheral lymphoid organs (e.g. lymph-nodes) in the course of immune responses (Nowell 1960). Thus, by the mid-1960s the framework within which immunological ideas could be set was better defined. The demands on those who presumed to offer unifying syntheses had become more restrictive. The loose hand-waving that might satisfy critics in the 1950s would less likely be tolerated.

    In the course of doctoral studies (1964-1967) in the Department of Biochemistry, Cambridge, I used lectins as 'antigen analogues' to stimulate cultured lymphocytes. Immune responses in vivo were known to be antigen dose-dependent, with inhibition of responses at high antigen doses (Mitchison 1964). Thus an antigen seemed capable of giving at least two, concentration-dependent, signals to an organism, one leading to an immune response, and one leading to response inhibition. Could this play out at the level of individual cells? Could inhibition by high antigen concentrations relate to the way an organism's own antigens ('self') prevented autoimmune reactivity? With these thoughts, I paid particular attention to lectin dose. If lectin bound to lymphocytes, then an increase in lymphocyte concentration should increase lectin requirement. But this was not found. The lymphocyte response was dependent on the ratio of the quantity of lectin to the quantity of serum present in the culture medium. This observation (in January 1966) was briefly reported (Forsdyke 1966a). A simple explanation, supported by subsequent studies, was that lectin-binding sites were present both in serum and on cells, but since serum sites were in great excess, they served to buffer cell-borne sites against reaction with lectin. Only by virtue of the cell-lectin interaction would peripheral lymphocytes be activated to enlarge and proliferate (signal one), or die (signal two; Milthorp and Forsdyke 1970; Forsdyke 1980). Thymus lymphocytes were not activatable (Forsdyke 1969a).

     It was a small step to go from this, to the idea that antibody-like receptors at the surface of a lymphocyte could be buffered against reaction with specific antigen by the corresponding free natural antibodies in the body fluids around it. The natural antibodies that had so excited Jerne would serve not only to bind an antigen, hence facilitating its disposal, but would also prevent its interaction with specific lymphocytes. Whether a lymphocyte was activated by specific antigen was determined by the ratio of the concentration of antigen to the concentration of the corresponding natural antibody. Thus, the signal given to a lymphocyte could be modified either by variation in antigen concentration (numerator), or by variation in antibody concentration (denominator). Within this framework, there emerged explanations for various immunological phenomena in terms of the delivery of one of two signals to a lymphocyte - one stimulatory and one inhibitory. This dispensed with the postulate that whether antigen stimulated or inhibited lymphocytes depended on their stage of development (Burnet 1959), or that stimulation required a cellular cofactor (Medawar 1963).

A Few New Things

First mention of the new hypothesis is found in my diary entry for 23rd April 1966.4 Following an examination of the relevant literature, a later entry (19th June 1966) declared that 'many main features of my ideas have already been presented by Jerne 1955, and Lederberg 1959.' However, I added that there were 'a few new things to say.' A paper setting out the 'few new things' was kindly read by two Cambridge biochemists well versed in immunology (Cesar Milstein and Alan Munro). They advised that theories were for old guys in their dotage and that at my stage of career it would be better to do experiments. Apart from this, while displaying no enthusiasm, they had no major criticisms. I formally submitted the paper from the Department of Biochemistry to Nature on the 16th of September, and the hypothesis was outlined at a scientific meeting at Oswestry a week later (Forsdyke 1966b).

     On my return from Oswestry, I learned of the policy that papers submitted from the Biochemistry Department had to be approved, prior to submission, by the Head, Frank G. Young. As a matter of courtesy, I had dropped off a copy of the paper to his office, together with a paper on the lectin-serum interaction that I had submitted to the Biochemical Journal. Young allowed my submission to the Biochemical Journal to stand (Forsdyke 1967). However, after consulting an immunologist - Robin Coombs of 'Coombs test' fame - Young insisted (28th September) that I withdraw the Nature paper. At my request the Editor returned it.5

    At a subsequent meeting Coombs told me that the paper was not clear and advised that I leave it a few months and then reconsider. My diary records (29th October 1966) that I sent copies of the paper to various immunologists - Frank McFarlane Burnet, Peter B. Gell, James Gowans, John Humphrey, Niels Jerne and Joshua Lederberg. Replies were received from all except the last two. Burnet replied promptly with encouragement. Humphrey invited me to Mill Hill for a discussion (17th November).   

    The theory formed a major part of my Ph.D. thesis, submitted in November 1966 and examined (5th May 1967) by Humphrey (external examiner) and Kenneth McQuillen (internal examiner). They required extensive revisions and less emphasis on theoretical aspects. The revised thesis was submitted on 2nd September, by which time I had relocated to the Institute of Animal Physiology, Babraham, Cambridge.

A Short Version

Meanwhile, prompted by Coomb's advice, I had written a short version of the paper citing my doctoral thesis where 'a more extensive hypothesis' would be found.  My diary notes (24th September 1967): 'I have written - - a very simple, and rather popular theory paper - taking the key point of my first paper and adapting it to the analogy of the distinction between "self" and "not-self" in a liquid scintillation counter.'6 On learning (2nd December 1967) that my Ph.D. thesis had been accepted, I submitted the paper to the Lancet, giving my home address, not an institutional address. The paper was accepted without demur (13th January 1968). I received the page proofs shortly thereafter (23rd January), and the paper was published on the 10th February (Forsdyke 1968).

    Later in the year, after relocation to Canada, my diary records (24th November 1968) that, prompted by the appearance of a different two signal hypothesis in Nature (Bretcher and Cohn 1968), I decided to publishing the 'more extensive hypothesis.' The appendix of my thesis, with minor modifications, was duly submitted to the Journal of Theoretical Biology (13th December 1968). Six months later (8th June), I was informed that, while acceptable to one reviewer, the other had criticisms. I responded to the criticisms and the paper was accepted (Forsdyke 1969b). The response was somewhat underwhelming. However, Podolsky and Tauber (1997, p. 400) later noted that one of the authors of the Nature two signal paper had retrospectively credited my Lancet paper as having 'put us on the right track,' but had added that 'it provided us with only a mere glimmer of the principle' (Cohn 1989; 1994).7 To date (2010) the 1968 paper has received only six independent citations, and the 1969 'more extensive hypothesis' only two. Nevertheless, as will be set out here, it was my two signal hypothesis that launched the affinity/avidity model with the now widely accepted view that the repertoire of lymphocyte receptor specificities is shaped by processes of both negative and positive selection.

Affinity/Avidity Model

While not documented, I recollect that it was during the correction of the page proofs of the Journal of Theoretical Biology paper (perhaps in October 1969) that I began to develop what is now known as the affinity/avidity model8 for the selection of lymphocyte repertoires. The basic idea was that the antibody-like receptors borne by lymphocytes could vary in their affinity for antigen. A low antigen concentration would mainly stimulate lymphocytes with high affinity receptors. But a high antigen concentration could stimulate lymphocytes with low affinity receptors (first signal), while giving a second signal (inhibition) to lymphocytes with high affinity receptors. My two signal hypothesis had suggested a way (by removing the natural antibody buffer) that those with high affinity for self antigens could just receive the second signal (negative selection), even at low antigen concentrations, while those with low affinity for self antigens could still receive the first signal (positive selection).

    Some notes dated 11th July 1971 give the key elements of the new model.9 But, having left Cambridge with the admonition ringing in my ears - stop thinking and do experiments, and being required for the first time to coax funds from granting agencies with plausible stories that did not stretch the imagination, it made sense to follow the Cambridge advice. In that period my publications became solidly grounded on the experiments in my laboratory.

    A paper reporting antigen dose-response relationships in lymphocyte cultures was submitted to the Journal of Experimental Medicine in April 1971. It was returned without having been sent for review. A succession of rejections followed (Journal of Immunology, Cellular Immunology, Biochemical Journal). Experiments continued and the data soon outgrew the original paper. In 1973 three interrelated papers were submitted to Immunology (3rd February) and were collectively accepted (28th March; Forsdyke 1973a, b, c). In these papers positive selection of lymphocyte repertoires was briefly referred to, but it was becoming apparent that a regression to bold public theorizing was in order.

    Just as factual restrictions on the scope of theorizing had increased dramatically in the decade between Jerne's natural selection theory and my two signal hypothesis, so between the mid 60s and the mid 70s there were even greater advances. These included, the sequences and structures of antibodies (Hilschmann and Craig 1965), the sub-division of small lymphocytes into cooperating populations (dubbed 'T' to indicate an origin in the thymus and 'B' to indicate origin in the bone marrow; Claman et al. 1966), and the finding that immunological responsiveness was influenced by cell surface components that had a major influence on whether grafts would be accepted between members of the same species (major histocompatibility complex antigens, MHC antigens; Benecerraf and McDevitt 1972; Bodmer 1972).10

    Furthermore, studies of the reactivity ('alloreactivity') of lymphocytes from one organism, that had been injected into another member of the same species ('graft-versus-host reaction;' Cock and Simonsen 1957),11 had led Morten Simonsen to challenge the clonal selection theory. The frequency of alloreactive cells was 'too high to be compatible with the orthodox version of clonal selection' (Nisbet et al. 1969). In other words, organisms seemed to have put all their eggs into the alloreactivity basket. Their repertoires were so misshapen that insufficient reactivity was left for the universe of other antigens that might be encountered. Thus, as later expressed, 'the thymic education of T cells provides them with blinkers' (Simonsen 1990).

Jerne's Defense of Clonal Selection

Now approaching his sixtieth birthday and director of the newly founded Basel Institute for Immunology, Jerne met his fellow Dane's challenge with a new theory: 'One of my basic intentions in formulating the present theory was to save the clonal selection theory from the consequences of Simonsen's argument' (Jerne 1970, p. 359). Since skin grafts between parents are always rejected, it seemed likely that their child, containing MHC antigens from both parents, would need to define 'self' afresh. Accordingly, the orthodox version of the clonal selection theory required diverse lymphocytes, each with a distinct antigen specificity, to be randomly generated during the life of an individual organism. At the outset, those reactive with an organism's own antigens would be eliminated. This orthodox version placed no onus on the variable genes themselves, save that their sequences and structures should not have mutated over evolutionary time in a way that would impede subsequent diversification, on a cell by cell basis, over somatic time. This would then permit the generation of a spectrum of specificities, one for each lymphocyte. Lymphocytes that emerged from this self/not-self discrimination filter would suffice to confront the universe of foreign antigens.

    Jerne begged to differ. His speculations were first released as a privately circulated 'samizdat' document,12 then as a World Health Organization (WHO) document (Jerne, 1969), and then as part of the proceedings of a conference held at Brooke Lodge (May 1970), where there was extensive discussion by Simonsen and others (Jerne, 1970). A submission to the Proceedings of the National Academy of Sciences was declined because it was too long (Soderqvist 2003, p. 265). The final version came to immediate prominence in 1971 as the first paper in the first issue of the European Journal of Immunology (Jerne 1971). This was the year of the First International Congress of Immunology, which can be seen as culminating Jerne's efforts, through WHO, to further international cooperation in immunology (Soderqvist, 2003, p. 229).

     Jerne proposed that the generation of diversity in a 'mutant breeding organ' (thymus or bone marrow) would have been driven by self antigens - in particular, by self MHC antigens: 'I don't really want to define too precisely the set of cell-surface antigens against which antibodies are determined by the v-genes in my theory. But let us try the assumption that the surface antigens involved are a certain set of major histocompatibility antigens' (Jerne 1970, p. 349). Thus, the DNA encoding antibody variable regions (v-genes) would have been selected over evolutionary time to determine reactivity with MHC antigens. Organisms that did not display sufficient reactivity would have been eliminated by natural selection. Germ line DNA was not a blank slate upon which somatic mutational processes would subsequently act. DNA already encoded MHC reactivity. The repertoire was biased towards reactivity with MHC antigens.

    Jerne acknowledged: 'It is easiest to understand the presence of a set of germ-line v-genes if its maintenance were subject to a strong evolutionary selection pressure' (Jerne 1971). Yet, what could that selection pressure be? 'I assume that antibodies directed against self components on cell surfaces have some important function in ontogeny, namely in the cell to cell recognition that is needed for the formation of specialized tissues and for morphogenesis.' This was more simply stated in an earlier version (Jerne 1970, p. 349): 'I assume than an embryo cannot even develop, let alone an individual survive, unless its cells can make antibodies that fit to the surface antigens of the individual.' That Jerne was somewhat out of his depth here, is indicated by an allusion in the final paper (Jerne 1971) to the offspring of mules (which, being sterile, do not have offspring). If we forgive his sweeping assumptions (and many were so inclined),13 it seemed that, in one fell swoop, Jerne had explained the 'Simonsen phenomenon.' Since the distinction between B cells and T cells had only recently emerged, it was easy to suppose that the theory applied 'equally to cells that make antibodies for secretion [B cell lineage], and for those cells that incorporate the antibodies only on their surfaces as receptors [T cell lineage]'14 (Jerne 1970, p. 345).  

    There were added subtleties. For any individual, two lymphocyte subsets were postulated. The Simonsen phenomenon (alloreactivity) was due to a subset with receptors directed against the MHC antigens of the species that the individual did not possess (allogeneic histocompatibility antigens; subset A).15 These receptors were directed against all the MHC 'cards' that nature had available to deal out, less those that had been dealt out to that particular individual. Thus, the A subset genes, by definition, did not encode reactivity with 'self' MHC antigens. But the individual, while not reacting against its own antigens, had to develop reactivity against the universe of other possible antigens (not necessarily MHC antigens) that might be encountered. This was where the second subset came in. Lymphocytes of the second subset started out with receptors directed against the MHC antigens that the individual happened to have inherited from its parents (subset S). Jerne postulated that the corresponding v-genes would be subject to mutation in the mutant breeding organ, so that the affinity of lymphocyte receptors for self MHC would erode and new affinities for foreign antigens that might later confront the organism, would randomly arise. If a cell failed to mutate sufficiently (i.e. it retained reactivity with self-MHC) it would be destroyed (negative selection).

     It should be noted that there was no suggestion of selection for self reactivity (positive selection; Forsdyke 1995b). For Jerne, a cell of subset S: 'proliferates, perhaps because a hormone stimulates the proliferation of all stem cells entering the thymus. Possibly, the histocompatibility antigens in the thymus which fit to cell receptors provide additional stimulation. I assume, however, that for this same reason none of the cells of this "forbidden" clone will be permitted to leave the thymus as antigen-sensitive cells, but that they will eventually all die out' (Jerne 1971). Only cells of subset S that could mutate would survive, so that: 'finally, cells will arise that have entirely lost their fit to the histocompatibility antigens of the individual itself.' Thus, there was ongoing proliferation in the thymus and it was the absence of negative selection that, in Jerne's view, allowed cells with v-gene mutations to survive. The role of intrathymic self-histocompatibility antigens in driving the proliferation of the S subset was an afterthought - a way of getting the mutations that would not be seen in subset A, even though these cells would also be proliferating. There was no implication of the S subset being positively selected somatically for the ability to react with not-self histocompatibility antigens (the role of the A subset as determined in the germ-line).

     Jerne (1971) concluded: 'The restriction of ontogenic selection to random mutants of cells expressing v-genes of subset S thus determines both the responsiveness to certain types of antigen and the range of antibody specificities that an individual animal can produce, so that, indirectly, these properties are under dominant control of histocompatibility genes.' The possibility that development from an initially biased state (anti-self MHC) might so restrict the range of final specificities that responses to some pathogens might be compromised, was not entertained. Nor was there further clarification of 'indirectly.' I met Jerne briefly at a Woods Hole conference in September 1973, but I cannot recall that we discussed science.

Positive Repertoire Selection

There is no record as to when I began writing a new theoretical paper. Not the least of many distractions was Watergate, famous for: 'What did he know, and when did he know it?' The Journal of Theoretical Biology records that my paper was received 28th May 1974. My diary records (4th January 1975) that the paper was accepted 'after 5 months delay without explanation.' It was published in July (Forsdyke 1975).

     Like Jerne's, my paper treated lymphoid cells generically without a distinction between T and B lymphocytes, but there was no division into subsets. My model was derived from the first principles set out in my two signal papers, and from consideration of the probability that a pathogenic microbe (e.g. virus) would usually adapt by mutation quicker than its host. A microbe that could, in one step, mutate one of its surface antigens from a form that was not-self with respect to its host, to a form that was self with respect to its host, would have largely overcome the host's immune defences with respect to that antigen. It could then exploit the 'holes' in the repertoire that had been created by the elimination of self-reacting lymphocytes. However, mutation is generally a stepwise process. If a microbe (not-self), by mutating a step towards self along the path from not-self to self, could secure a selective advantage, then the mutant form would come to dominate the microbe population. If a microbe from this mutant population, by mutating a further step along the path, secured a further advantage, then this new mutant form would, in turn, come to dominate the population. Thus, an average member of the microbe population would progressively become better adapted, to the detriment of the host.

    This supposes that progressive mutation along the not-self-to-self path would be increasingly advantageous to the microbe. However, the advantage would be lost if, as it mutated closer to host-self, the microbe encountered progressively stiffer host defences. Thus, positive selection of lymphocytes for specificities that were very close to, but not quite, anti-self, could be an important host adaptation providing 'a barrier opposing the progressive evolution of the surface determinants of a pathogen into forms identical with the surface determinants of its host' (Forsdyke 1975). To emphasize this proximity to self, positive selection was described as the somatic generation of repertoires that would have been preselected to respond against 'near-self' antigenic determinants. Thus, MHC involvement would have been an automatic consequence of the positive selection of 'anti-near-self' cells during their initial maturation. The ideas of positive selection and of its mechanism came as one conceptual package. By virtue of their priming by self, some of the anti-near-self cells would cross-react with foreign MHC antigens, so would correspond to Jerne's A subset. The need to take into account total population-size homeostasis was also emphasized, so that an increase in a population of one affinity would require proportionate decreases in other populations.

'Near Self' or 'Altered Self'?

Shortly before the submission of my paper, there appeared in Nature a paper by Rolf Zinkernagel and Peter Doherty (1974). Extending earlier work on MHC-restriction of B and T cell cooperation, they had shown that T cell-mediated cytotoxicity was also MHC-restricted. Their paper, which to date (2010) has received 1515 citations, was the basis of their Nobel prize (Zinkernagel and Doherty 1997). Instead of my term 'near self,' which emphasized how close an antigen might be to self, they had used the term 'altered self,' which emphasized the fact of a difference from self. The relative merits of the two terms are discussed elsewhere (Forsdyke 2005).

     The paper of Zinkernagel and Doherty (1974) does not appear among my cited references (Forsdyke 1975). While not documented, I recollect that I read it some time after its publication date (19th April), and prior to submission of my paper (about 20th May). Since it supported my viewpoint, I considered adding it to my cited references, but did not want to imply that my paper was in any way derivative of theirs. While treating host cell surface antigens generically, I had already indicated the possibility of MHC involvement both by citing two MHC papers (Benecerraf and McDevitt 1972; Bodmer 1972), and by mentioning, not in a way that can be deemed prescient, a possible association of pathogen surface antigenic determinants with host cell surface components - a theme later developed more extensively (Forsdyke 1991). The term 'near-self' is in my notes dated July 1st 1971, and the concept was touched upon in 1973: when discussing '"self" antigens capable of stimulating low specificity anti-self cells,' I remarked that: 'A high concentration of such low specificity cells would be predicted from theoretical considerations previously advanced'(Forsdyke 1973a).

      A decade later the differential affinity/avidity model was independently introduced for T lymphocytes by Jonathan Sprent (Lo and Sprent 1986; Sprent and Webb 1987). Although for some time opposed by the 'peptide' model (Claverie and Kourilsky 1986; Marrack and Kappler 1987), it eventually became widely accepted as applying generically to both T and B lymphocytes (Gaudin et al. 2004; Wen et al. 2005). Thus, Janeway (2001) concluded: 'Both the mature, naive T cell repertoire and the mature, naive B cell repertoire are generated by interaction with self-ligands rather than non-self ligands. These self ligands can signal B and T lymphocytes to mature and to survive.' Cancro and Kierney (2004) pondered 'the underlying biological rationale' of the positive selection of B and T lymphocytes, and the role of 'unaccounted structural space' (i.e. holes in lymphocyte repertoires). They envisaged the development of 'subthreshold self reactivity" (i.e. near-self), which would minimize 'potential evasion by rapid microbial evolution.' This came close to the case made in my 1975 paper that, to date (2010), has received only 4 independent citations.  


A published theory may not necessarily be first, but it can be foundational (in a constructive sense). Sometimes it can be both - the classical example being Gregor Mendel's discovery of what we now call genes. Mendel's paper (1865) later became foundational even though it only began to influence others in 1900. In the interim no alternative foundational challenger had emerged (Cock and Forsdyke 2008). On the other hand, Paul Ehrlich (1900), although first in many respects, seems not to have been foundational in terms of influencing those who opened up immunology in the 1950s (Forsdyke 1995a). Yet surely science would better advance if all firsts were foundational? Rather than dismissing non-foundational firsts as premature (Barber 1961; Zuckerman and Lederberg 1986), an important task for historians of science would seem to be (i) collecting cases of temporal gaps between first and foundational, (ii) for each case determining the reasons for the gap, (iii) comparing cases in search of common elements and, if such are found, (iv) making conclusions available to science policy advisors (Forsdyke, 2000). In this way, taking immunology as an example, we might hope to accelerate progress towards effective treatments of autoimmune diseases (e.g. rheumatoid arthritis), and infections (e.g. AIDS).

     From a 'presentist' perspective (Harrison 1987), Jerne's first theoretical immunology paper (the natural selection theory; Jerne, 1955) later appeared primitive relative to the sophisticated cellular hypothesis advanced by Ehrlich a half century earlier (Forsdyke 1995a). Indeed, so rapid were developments in molecular biology that, by the time of publication Jerne's proposed mechanisms were already obsolete (Cohn 1994). Protein directly begetting protein (more antibody) was inconsistent with much of genetics and molecular biology. If a cell could somehow 'read' a protein and turn that information into nucleic acid, Jerne's idea might have worked, because nucleic acid can beget nucleic acid, and that nucleic acid can then beget more of the protein. But no mechanism for directly 'reading' a protein into nucleic acid was known then, or has since emerged.

     Yet Jerne's natural selection theory has proved both first and foundational in two important respects - he overcame 'Ehrlich's dilemma,' and he pointed out the need for a randomization process to generate potential reactivity to a wide range of antigens. Influential contemporaries (e.g. Linus Pauling) were then wedded to the idea that a foreign antigen 'instructs' a cell to make complementary antibody. To flatten any opposition, they needed only to point to Ehrlich's dilemma - it was inconceivable that an organism could be prepared in advance for the infinite range of antigens that might possibly present themselves (Ehrlich 1900). Indeed, it was not until Burnet brought Jerne's paper to his attention, that Lederberg saw a way round this problem (Lederberg 1994).

    Jerne's studies of the avidity of serum antibody activity after immunization had revealed to him that 'among the population of circulating globulin molecules' there could be some 'better-fitting' an antigen than others. There could be a '"low grade" antibody of low combining capacity' and a '"more avid" antibody of high combining power.' So the affinity of an antibody for an antigen was a matter of degree. 'The number of specific configurations which a globulin molecule can exhibit is large' and 'since normal mammalian serum contains more than 1017 globulin molecules per milliliter, these may include a million 1011 fractions of different specificity. This would seem an amply sufficient number.' So 'there will - - be fractions possessing affinity toward any antigen to which the animal can respond.' Ehrlich's dilemma was false (Jerne, 1955). And how might an organism arrive at an 'amply sufficient number'? Jerne further proposed that: 'Somewhere in the beginning - - we have to postulate a spontaneous production of globulin molecules of a great variety of random specificities in order to start the process.' This might occur in 'a specialized lymphoid tissue, such as the thymus.'

    What remained puzzling is why Jerne did not go further. Jerne had invoked 'multiplication of the cells' that made antibody, and in 1995 I assumed  that, had he known of Ehrlich's side chain theory, he would have quickly realized that his proposed randomization process could have occurred at the cellular level (Forsdyke 1995a). Others were already toying with the idea. It was in the air. Indeed, in his biography Soderqvist (2003, p. 221) related that a few months after publication of the natural selection theory a young colleague, Jorgen Sparck, had suggested that cells were the selection unit, but Jerne 'was evasive and did not accept it.'

     It is now apparent (Soderqvist 2003, p. 179) that, in an early draft of the 1955 paper, Jerne had indeed discussed Ehrlich's theory, but had omitted this from the final version. Jerne had conceded to Soderqvist that he might have been unconsciously influenced by his prior reading of Ehrlich's papers but, as far as he was aware, the key idea came out of the blue. Soderqvist speculated that Jerne 'wanted to be unique, that he opted for originality rather than displaying his connectedness with tradition.'

    The fact that Jerne did know of Ehrlich's work is surprising since it seems such a short step to go from the selection of antibodies to the selection of cells. Jerne did not take that step, perhaps because he suspected that his solution of Ehrlich's dilemma would seem less cogent if the diversifying unit were cellular. Within an organism there are far fewer lymphocytes than globulin molecules. If each cell corresponded to one distinctive antibody specificity (one cell one antibody) then, although the antibody combining region might adopt a large 'number of specific configurations,' this might not be sufficient for the organism to confront the universe of potential antigens? There would be more holes in the repertoire that a pathogen could exploit, and perhaps Jerne was not prepared to consider this possibility.

    Jerne's second major theoretical immunology paper was his defense of clonal selection (Jerne 1971). It was a first in suggesting that germ-line variable region genes had been preselected over evolutionary time to encode reactivity with the MHC antigens of the species, but it was not foundational in two respects: his explanation of why there should have been this preselection was vague, and later investigations of antibody receptor structures gave only a hint of preadaptation for MHC reactivity (Huseby et al. 2004; Scott-Browne et al. 2009; Roomp and Domingues 2011). Thus, germ-line v-genes, at least in the antigen-combining regions, are essentially blank slates. It is mainly after somatic variation and selection for MHC-reactivity, that such reactivity becomes evident. Jerne's assertion that 'germ-line v-genes code very precisely for antibodies that fit to a certain set of histocompatibility antigens, i. e. that these postulated genes determine antibodies that fit to the surface antigens of cells of the same animal species,' was incorrect. However, in the years that followed, his 1971 paper received many citations. It might be thought that it was foundational because it had focused attention on the Simonsen phenomenon and MHC antigens, but these were already subjects of high immunological interest.

    In contrast, my paper presenting the affinity/avidity model (Forsdyke 1975) has, to date (2010), received only 4 independent citations. Since it cited Jerne's 1971 paper, a naive future historian might regard his paper as foundational in this respect. However, as set out here, my model was independently developed from the premises set out in my earlier two signal papers, which might accordingly be regarded as foundational. Yet, although it would now appear that my affinity/avidity paper (Forsdyke 1975) was a first, it was not foundational in that others (i.e. Sprent and his coauthors) developed similar models while being unaware of mine. To date (2010) the paper of Lo and Sprent (1986) has received 305 citations, Sprent and Webb (1987) 210 citations, and a later review (Sprent et al. 1988) 408 citations. Podolsky and Tauber (1997, pp. 331-332) imply that positive selection became apparent in 1986.

    Jerne's third major theoretical immunology paper (Jerne 1974) presented his 'network' theory (Soderqvist 2003, pp. 273-277). The details of this and of its apparent downfall need not concern us here, save for a recent historical comment (Tauber 2010): 'This theory enjoyed a great vogue from its presentation in 1974 through the 1980s - - . That major textbooks completely omitted any mention of Jerne's network by the late 1990s reflects how other theoretical concerns vying for dominance signify a key conceptual struggle within the discipline that dates to its origins.' Thus, like his 1971 paper, it now seems to have been first, incorrect, and non-foundational.

Concluding Remarks 

I have here considered the being first role, and the foundational role, of immunological theories over the period when the clonal selection theory was being established and extended (1955-1975). New observations and theories that followed this period have been considered only to the extent that they document the foundational impact of the earlier theories. A central figure in the paradigmatic transition was Niels Jerne. His natural selection theory of antibody formation (1955), although mechanistically primitive, was both a first and foundational in that it resolved Ehrlich's dilemma, predicted a randomization process by which antibody repertoires would be generated, and greatly influenced contemporary scientists. For jolting Burnet out of his Lamarckist mindset (Podolsky and Tauber 1997: p. 36) to embrace a Darwinian selective model, we remain in Jerne's debt.

    This, and Jerne's later speculations (1971, 1974), led the chairman of the Nobel Prize committee to conclude that his 'visionary theories caused modern immunology to make major leaps of progress. Several concepts in immunology now considered as self-evident have their roots in some of his pioneering thoughts' (Wigzell 1984). '"The king of theorists has finally been crowned" exclaimed - - evolutionary geneticist Susumo Ohno' (Soderqvist 2003, p. 283). A leading immunologist later declared that 'Jerne first invented positive selection,' but added that although 'his original model was simple, attractive and insightful,' it had 'predicted several things that have since been shown to be wrong' (Matzinger 1993). When reviewing 'Jerne's legacy,' other leading immunologists concluded that most of his ideas 'have turned out to be incorrect' (Huseby et al. 2004). This was because 'he was missing essential information.' They believed that, although 'he and others correctly anticipated the phenomenon of central tolerance, he could not have predicted the idea of positive selection' (my italics). I have here argued to the contrary that (i) Jerne did not 'invent' positive selection, but (ii) information to make that prediction was available. While, in future, it may be determined that my chain of reasoning - from information to prediction - was naive, I have shown here that the prediction of positive selection was possible even if by some perhaps incorrect chain of reasoning.

    Although one can agree that Jerne's later ideas (1971, 1974) were ingenious and, indeed, 'visionary,' it does not now appear that they were correct visions. As more personal accounts of the protagonists become available (e.g. Simonsen 1990, Cohn 1994; Zinkernagel and Doherty 1997; Bretscher 2004), historians may come to question whether 'major leaps of progress' resulted (Radick 2008). An alternative scenario is that his 'pioneering thoughts' led immunologists down blind alleys, thus diverting resources from projects that might have advanced knowledge more expeditiously. Following the establishment line is likely to guarantee research funds; failure to follow that line can be professionally hazardous, especially for young researchers (Forsdyke 2000). In this respect we should note that Jerne was 'critical of the prevailing research policy, which stimulated young scientists to sequence a bit of a gene but prevented them taking on more theoretical tasks' (Soderqvist 2003, p. 288). If we wish for 'fewer instances of rediscovering the wheel' (Brent 1997, p. xi), we must take into account all opinions, young and old (Cock and Forsdyke 2008, pp. 643-666).


Queen's University hosts my theoretical immunology webpages where some of the cited references, including that of Ehrlich, may be found.


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1 Typically a virus (antigen) provokes the synthesis of immunoglobulins (antibodies) that bind the virus and destroy it. The clonal selection theory postulated that one cell of the immune system (lymphocyte) corresponds to one antibody specificity (e.g. specificity for virus A, but not for virus B). An antigen would select a particular cell from the pre-existing repertoire of cells. This cell would then multiply into a clone that would secrete its specific antibody into body fluids (e.g. lymph and blood plasma).

2 An organism can prepare an antibody repertoire randomly in the hope that, by chance, there will be at least one antibody that can combine with an invading foreign antigen. Alternatively, the organism can, in advance, shape the repertoire taking into account some property common to certain antigens. This shaping can be said to bias, or restrict, the repertoire. If the antigens are MHC, then the repertoire is said to be 'MHC-restricted.' 

3 An organism has its own antigens. There is a need to suppress a cell that can make antibody against these ('self'), and to stimulate a cell that can make antibody against foreign antigens ('not self'). Thus, an antigen has the potential to give one of 'two signals' to a lymphocyte, which hence is selected either positively (clonal expansion) or negatively (clonal deletion or suppression). 

4 Photocopies of diary entries are in Queen's University Archives. These may also be viewed at 

5 A copy of the paper submitted to Nature in 1966 (F9264) is in Queen's University Archives. 

6 I learned of the two signal mechanism for distinguishing signals in a liquid scintillation counter from a manufacturer's technical manual, probably read in 1965. In 1967 I saw this as a helpful marketing metaphor, but do not believe it influenced the emergence of my two signal ideas in 1966.

7 I later discovered that Bretcher was a contemporary at Cambridge. As far as I am aware, we did not meet. I had no communication with Cohn or his coworkers until the 1990s.

8 An antibody may bind an antigen because of the affinity of an individual combining site, but the observed strength of binding (avidity) may reflect binding at multiple sites. Since it is difficult to distinguish these, the model is referred to as the affinity/avidity model. To simplify, this paper refers mainly to affinity. Likewise, often 'antigen' is used where the term 'antigenic determinant,' or 'epitope,' might be more appropriate.

9 Photocopies of dated notes are in Queen's University Archives. These may also be viewed at There are other notes,  but these are not clearly dated.

10 For the synthesis of most antigens, the species 'pack' usually contains only two gene 'cards.'  You hold two - one from your father and one from your mother. So these 'cards' can be either the same (e.g. YY or ZZ), or mixed (e.g. YZ). On the other hand, for the synthesis of MHC antigens the species 'pack' contains many 'cards' (e.g. A, B, C, - - X, Y, Z), but you still can hold only two (e.g. BX). So, if genetic shuffling is thorough (unbiased), it is unlikely that the two MHC antigen 'cards' you inherited from your parents will be the same. This means that the differences between graft and host that determine graft rejection are mainly differences in MHC antigens.

11 When skin from one individual (donor) is grafted to another individual (host), it is rejected by host lymphocytes ('host-versus-graft reaction'). When lymphocytes from one individual (donor) are injected ('grafted') into another individual (host), the lymphocytes attempt to reject their host ('graft-versus-host reaction').

12 Jerne, N. K. 1969. The generation of self-tolerance and of antibody diversity. A copy of this privately circulated document, bearing the stamp 'Dr. Melvin Cohn, Aug 11 1969,' was received by the present author in October 1970 by way of New Zealand immunologist, John Marbrook. A copy has been placed in Queen's University Archives. This is probably the document referred to by Soderqvist (2003, p. 262): 'Jerne completed his manuscript in the beginning of August 1969 and circulated it to his peers.' Thus, there is probably an identical copy in the Archives of the Royal Library, Copenhagen (Soderqvist 2003, p. 329).

13 Bodmer (1972) disagreed on population genetic grounds: 'A principle, almost insurmountable difficulty with Jerne's hypothesis - - is that it seems to require strict parallel evolution at the population level of histocompatibility antigen genes and immunoglobulin v genes. Thus, - - as soon as a new histocompatibility antigen arises by mutation or recombination, the corresponding germ line v gene coding for the antibody specificity directed against this new antigen must somehow almost immediately spread through the whole species.'

14 Cells of the T cell lineage (cytotoxic T cells), by virtue of their antibody-like surface receptors, can react with antigens at the surface of target cells and destroy the cells.

15 Jerne postulated subsets A an S. Subset S would be 'cards' BX in the example above, and subset A would be the remaining 'cards' in the species pack (A, C, D, - - W, Y, Z).

End Note June 2011 Eichman's Network Collective

Unfortunately too late to be mentioned above, Hidetaka Yakura (2011 Bioessays 33. 552-554) draws attention to a book by one of Jerne's collaborators, Klaus Eichmann (2008) entitled: The Network Collective: Rise and Fall of a Scientific Paradigm. This nicely complements my paper since it focuses on the idiotype network theory (INT), which is only touched on briefly here. The variable region of each antibody molecule has a unique potential antigenic determinant (idiotype) corresponding to its specificity. Jerne's INT proposed that this determinant can be recognized by the specificity region of another antibody molecule of the same individual, and the latter specificity region can, in turn, be recognized by the specificity region of another antibody of that individual, and so on. Unlike Eichmann and many others, I dismissed Jerne's network ideas at the outset for the simple reason that immunologically competent cells arise sequentially. Cell A with the potential to make antibody A passes through the self-screening process and thereby antibody A becomes defined as self. When cell B with the potential to make antibody B arises, it passes through the same self-screening process, the only difference being that self now includes antibody A. If it is accepted, then B must be deemed not to interact with A (above a certain degree of affinity). So the network should fail, or peter out very rapidly. Yakura hails The Network Collective as "a product of Eichmann's extensive and incisive efforts to come to terms with [the negative aspects of] his academic life", which "gives us abundant first-rate information to reconstitute the recent controversial history of immunology and to reflect on scientific activities and their pitfalls."

End Note Jan 2012 MHC as Blank Slate Scenario

It would be nice if, without yielding an advantage to potential pathogens, an organism could orchestrate its germline so that, prior to positive selection, T cell receptor (TCR) variable regions would be better prepared to match the MHC. Thus, one lingering issue has been the extent to which MHC restriction is encoded in the germline, in keeping with Jerne's prediction (1971). The alternative is that TCRs are generated with a broad range of specificities, but only those lymphocytes with specificity for MHC undergo thymic positive selection. In other words, MHC specificity is imposed on a blank slate, as outlined above. In addition to the TCR, T cells have other receptors (known as CD4 and CD8, depending on the type of T cell), which are specific for a generic part of the MHC. Work in Alfred Singer's laboratory in the USA suggests that one or other of these coreceptors engages the MHC on the presenting cell at the same time as the TCR engages the MHC on the presenting cell. The coreceptors bring a critical intracellular signalling component (known as Lck) that permits the TCR to signal intracellularly that it has engaged an appropriate MHC complex. As long as the coreceptors do their stuff, pMHC specificity is assured. But, when the coreceptors are removed, a different T cell repertoire develops.

    It was concluded (Laethem et al. 2007), that "
coreceptor deficiency can uncouple thymic selection from MHC-recognition, and supports a different perspective of the function of CD4 and CD8 coreceptors in developing thymocytes and mature T cells. In addition, this study offers a remarkably straightforward explanation for how an MHC-restricted - - T cell repertoire is generated in the thymus."

    And later (Tikhonova et al. 2012), "
This study contradicts the perspective that MHC specificity is intrinsic to the structure of all - -TCRs and suggests the existence of a repertoire of - - TCRs with specificity for MHC-independent ligands that has never been examined. Thus, this study indicates that - - TCRs need to be screened for MHC specificity in the thymus in order to insure the generation of an MHC-restricted peripheral - - TCR repertoire."

   We should note, however, that the coreceptors themselves are encoded in the germline to match MHC. Whether it is the TCR, or the coreceptors, that confer a degree of MHC restriction, seems rather an academic point. There is germline encoding, and that was Jerne's message. It seems likely that TCRs evolved before the coreceptors, so probably there was a time when the unadorned blank slate scenario operated.

Laethem et al. (2007) Immunity 27, 735-750. Deletion of CD4 and CD8 coreceptors permits generation of alpha-beta T cells that recognize antigens independently of the MHC.
Tikhonova et al. (2012)
Immunity 36, 79-91. Alpha-beta T Cell Receptors that do not undergo Major Histocompatibility Complex-specific thymic selection possess antibody-like recognition specificities.

End Note Feb 2013 Mel backs off

Regarding footnote 7, concerning my 1968 Lancet paper, as quoted above, Melvin Cohn remarked that it had 'put us on the right track,' - - (Cohn 1989; 1994). However, in a new paper (Cohn 2012) he stated: "It was much later that we learned that Forsdyke (1968) in an elegant paper had at the same time also fingered the logic of the decision step as requiring two signals."

Cohn M. (2012) Experimental and Molecular Pathology 93, 354-364. What is so special about thinking; after all, we all do it!

End Note Mar 2013 Absense-of-Knowledge Postulate

Regarding the above segment on "Positive Repertoire Selection," Ronald Germain and his colleagues (2013) showed experimentally "that positive selection contributes to effective immunity by skewing the mature TCR [T cell receptor] repertoire toward highly effective recognition of pathogens that pose a danger to the host." Direct measurement of TCR self-binding activity being difficult, they used cell surface expression of a protein (CD5) whose level directly relates to TCR signalling strength - this being relatively high when TCR affinity for its target (i.e. MCH-peptide) is high. For various reasons, they were limited to TCRs on the T4 subset of T lymphocytes. They concluded by stating that "Our results - - provide an intuitive explanation for the effectiveness of thymic positive selection in predicting the unknown [my emphasis] and generating a useful T cell repertoire with which to combat infection in the absence of any 'knowledge' [their quotation marks] of which foreign antigens will be encountered."
     But Germain and his coworkers did not speculate on how the arrangement they so elegantly described might have evolved. What would have been the driving force that produced it? Their 'absence-of-knowledge' postulate seems to exclude the hypothesis described in these web-pages, which shows how that 'knowledge' could have been acquired - namely as a result of an 'arms race' between pathogen and host, the pathogen being able to adapt more rapidly than the host, and the host building a 'near-self' barracade to foil progressive pathogen adaptation.

Mandl JN. Monteiro JP, Vrisekoop N, Germain RN. (2013) Immunity 38, 263-274. T cell-positive selection use self-ligand binding strength to optimize repertoire recognition of foreign antigens. [For follow-up Mandl & Germain (2014) (Click Here)].

End Note Oct 2013 Two Signal Support

Huang et al. (2013) in the Mark Davis laboratory add further support to the view that fewer signals are needed to stimulate than to inhibit. In 2004 it was reported that this applied to CD8 T cells (Purbhoo et al. 2004): "For CD8+ cytotoxic T cell blasts, we have shown that one pMHC can trigger calcium signaling and that three or more pMHCs can lead to functional cell killing." The new paper shows thst CD4 T cells also respond to one signal: "We have demonstrated here that CD4+ naive T cells, T cell blasts, and memory T cells were able to secrete cytokines in response to even one pMHC. Furthermore, we found that cytokine production in three stages of T cell maturation was independent of ligand number beyond the first pMHC and thus they displayed a digital response pattern."

Huang J et al. (2013) Immunity 39, 846-857 A single peptide-MHC complex ligand triggers digital cytokine secretion in CD4 T cells.
Perbhoo et al. (2004) Nature Immunology 5, 524-530. T cell killing does not require the formation of a stable mature immunological synapse.

End Note Oct 2014 Positive Selection Support

Mandl and her colleagues in the Germain laboratory have gained evidence for, and are citing, the positive selection ideas introduced in Forsdyke (1975).

Vrisekoop, N. et al. (2014) Immunity 41, 181-190. Revisiting Thymic Positive Selection and the Mature T Cell Repertoire for Antigen.
Forsdyke DR (2014) arXiv Preprint server arXiv:1408.3321v1 [q-bio.CB] Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview.

End Note Aug 2016 Natural Antibody Blank Slate Scenario

Vale and colleagues (2016) support the view (Forsdyke 1975; Cancro & Kearney 2004), that the B-cell derived natural antibody repertoire is determined somatically and is not encoded in the germ-line.

Vale AM. et al. (2016) Front Immun 7: 296. The global self-reactivity profile of the natural antibody repertoire is largely independent of germline Dh sequence

End Note Sept 2017 Close to Self and Near-Self

In arriving at the major conclusion that "TCR selection against self-peptides has a minimal influence on the recognition of peptides which are 'close' to self,"  George and colleagues (2017) add yet further support to the "near self" viewpoint (Forsdyke 1975). A comment has been added to PubMed Commons.
[Added May 2018: Employing what might be vernacularly termed a "catch and kill" strategy, having lured comments to the PubMed Commons site for 5 years, the NCBI declared the "experiment" to have failed. Not only did the NCBI refuse to accept any more submissions to PubMed Commons, but it also cut the links from PubMed Abstracts to the comments. My comments were salvaged and may be accessed on the list of publications page. For more, see ASBMB Newsletter June/July 2018.]

George JT, Kessler DA, Levine H (2017) Proc Natl Acad Sci USA 114: E7875-E7881. Effects of thymic selection on T cell recognition of foreign and tumor antigenic peptides.

End Note Dec 2017 Non-Germ-Line Influence on TCR

Noting that "the structural basis of positive selection has long been debated," Marrack et al. (2017) show "that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor a and b chain and, surprisingly, dramatically affected by the non germ line encoded portions of CDR3 of the T cell receptor a chain." Among possible explanations, the paper is supportive of the "near self" viewpoint, citing the above mentioned paper of Vrisekoop et al. (2014), and Forsdyke (2015).

Forsdyke DR (2015) Immun Cell Biol 93: 297-304. Lymphocyte repertoire selection and intracellular self/non-self-discrimination: historical overview.
Marrack  P. et al. (2017) eLife 6: 30918. The somatically generated portion of T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor.

End Note May 2018 Germinal Centre B Cell Positive Selection

Acceptance of the existence of an immunological "repertoire that is much more restricted than would be expected from the random process of TCR somatic recombination," is growing. A paper in Science (13th April; Burnett et al. 2018) was summarised in an accompanying commentary (Kara & Nusssenzweig, Science (2018) "Redemption for self-reactive antibodies." Science 360: 152-153). They concluded that the paper furthered "our understanding of the biology of B cell anergy and provide a framework for thinking about why such cells might be allowed to persist in immune systems despite their self-reactivity." However, neither authors nor commentators used the term "positive selection." Rather than "near-self" the term "almost-self" was employed.

I posted the following comment, which is attached to the internet version of the Science paper.

Following the emergence of clonal selection ideas in the 1950s, the development of immune cell repertoires was seen to require the negative selection of self-reacting cells, with remaining cells exhibiting a wide range of essentially non-targeted specificities. Thus, when confronting the universe of possible not-self antigens, formidable in range, a potential host organism spread its resources widely. A proposed differential avidity mechanism, through which an organism could anticipate specificities needed for coping with microbial pathogens, introduced the less intuitive concept of positive selection. Be they of T or B lineages, immune cells were held to be positively selected for weak reactivity with self determinants (1).  While positive selection of developing lineages is now widely accepted for T-cells (2-6), its application to developing B-cells is less established (7, 8).

In highlighting "the value of retaining self-reactive clones as substrates for protective antibody responses," the new B-cell studies of Burnett et al. (10) strongly supports the case for the initial positive selection of B cells for responsiveness against what were termed "near self" antigens (1, 10-12). Moreover, unlike T cells, it is shown for B cells that there is then a further affinity maturation trajectory in germinal centers where, what are termed microbial "almost self" antigens, serve as a starting point for fine-tuning of specificity. Thus, self-reactive B cells were directed "down an alternative trajectory, which produced a higher final affinity for the foreign immunogen."

That immunological repertoires might be subject to positive selection arose by considering a potential host's anticipation of a pathogen's strategy. In the extreme, a microbe that, in one step, mutated one of its antigens from a form foreign to its host, to a form resembling the host, should prevail over host defenses with respect to that antigen. It could exploit the 'holes' in the repertoire resulting from prior negative selection. However, the situation is usually less extreme in that mutation normally occurs stepwise. A microbe that could gain a selective advantage by mutating a step toward self, along the path from non-self to self, would come to dominate the microbe population. A member of this mutant population that could secure a further advantage by mutating a further step along the path, would, in turn, come to dominate the population. Thus, members of the microbe population by progressive mutation along the not-self-to-self path, would become better adapted, to the detriment of their host. However, they would lose this advantage if, as they mutated closer to host-self, they encountered progressively stiffer host defenses. Thus, positive selection of lymphocytes for specificities that were very close to, but not quite, anti-self, should be an important host adaptation.


1.      Forsdyke DR (1975) Further implications of a theory of immunity. J Theor Biol 52: l87-l98.

2.      Sprent J, Lo D, Gao E-K, Ron Y (1988) T cell selection in the thymus. Immunol Rev 19 173-190.

3.      Bevan MJ, Hogquist KA, Jameson SC (1994) Selecting the T cell receptor repertoire. Science 264: 796-797.

4.      Vrisekoop N, Monteiro JP, Mandl JN, Germain RN. (2014) Revisiting thymic positive selection and the mature T cell repertoire for antigen. Immunity 41: 181-190.

5.      Madi  et al. (2014) T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity. Genome Res. 24(10): 1603-1612.

6.      Marrack et al. (2017) The somatically generated T cell receptor CDR3alpha contributes to the MHC allele specificity of the T cell receptor. eLife 6:e30918

7.      Cancro MP & Kearney JF (2004) B cell positive selection: road map to the primary repertoire? J Immunol 173: 15-19.

8.      Herzog S, Jumaa H (2012) Self-recognition and clonal selection: autoreactivity drives the generation of B cells. Curr Opin Immunol 24: 166-172.

9.       Burnett DL et al. (2018) Science 360, 223-226.

10.   Forsdyke DR (2005) 'Altered-self' or 'near-self' in the positive selection of lymphocyte repertoires? Immunol Lett 100: 103-106.

11.   Forsdyke DR (2012) Immunology (1955-1975): The natural selection theory, the two signal hypothesis, and positive repertoire selection. J Hist Biol 45: 139-161.

12.   Forsdyke DR (2015)  Lymphocyte repertoire selection and intracellular self/not-self discrimination: historical overview. Imm Cell Biol 93: 297-304.


End Note June 2018 Trump and Jerne

Hidetaka Yakura (see above) when reviewing The Network Collective mentions the negative aspects of Jerne's academic life. There are some interesting parallels with Donald Trump that become apparent when reviewing Soderqvist's writings. A 2002 paper (1) brings out relevant points. Both Jerne and Trump had wealthy fathers, whose continuing support gave them considerable flexibility. Both were late-bloomers (Spatzunders), arriving at the 'summits' of their careers after much wandering.  Both preached extreme gospels that "divided into sceptics and advocates" and the latter only slowly, if ever, realized their error. Both had, to say the least, unsavoury private lives. Both thought of themselves as persons "who would never accept being moulded by outer circumstances." Soderquist here refers to Musil's "A Man Without Qualities," and to a Greek philosopher capable of "adapting himself to place, time and person, and of playing his part appropriately under whatever circumstances." They were self-centred.  Jerne declared himself to be "more or less of the same opinion as all the people I talk with - - It's very easy, you only have to exercise your memory a little bit in order always to remember which opinion fits" the occasion. In other words, they were highly political and not ethically constrained.

1. Soderqvist T (2002) The life and work of Niels Kaj Jerne as a source of ethical reflection. Scand J Immun. 55: 539-545.


 End Note April 2019 For-the-record: Letter from FM Burnet 1966

Following the submission of "half century" papers by myself and Bretscher in the Scandinavian Journal of Immunology in 2018, I was invited to produce a paper for the journal's Discussion Forum, which would be commenting on Bretscher's contribution. This provided an opportunity to further elaborate on this 2012 paper. The following warm comments from FM Burnet on the 1966 version of my "two signal" paper may be relevant:

University of Melbourne, School of Microbiology, Sir Macfarlane Burnet.
6th October 1966

Dear Dr. Forsdyke,
   I have read your preprint with much interest and find very little to disagree with.

   For the past two years I have been working on a book to be called, "Cellular Immunology," which I hope to complete for publication by Melbourne University Press (in association with Cambridge University Press) before the middle of next year. Your paper comes remarkably close to being an abstract of the present first draft of the book. So I hope that if and when my book appears, you will absolve me of any suspicion of plagiarism!

   As for specific comments, I think your "randomization, recognition, stimulation and amplification" puts the elements of clonal selection very clearly. Incidentally, I prefer "clonal selection" to "natural selection" as differentiating it from Jerne's original "natural selection" in which cellular factors play no significant part and in making the distinction from the classical use of "natural selection" involving organisms undergoing germinal mutation and recombination, since we are concerned with somatic mutation or some equivalent process involving somatic cells.

   I prefer to think that randomization can occur anywhere in the sequence between the fertilized ovum and the plasma cell but mainly during the bone marrow stem-cell phase. The function of the thymus is to allow differentiation and what I am calling censorship, i.e., destruction of cells found to be capable of reacting with self-antigenic determinants.

   I am dubious about your suggestion of just two antibody molecules per cell. I prefer to think of receptors equivalent to the antibody combining site characteristic of the clone, and present in what I would leave in rather vague terms, as being in smaller numbers and less readily accessible than in cells which have once been committed by antigenic stimulation.

   I think there are minor differences in our approach to the 19S 7S relationship. Two points that I think will turn out to be vital are - (1) that antigen is only going to be an effective stimulus if it is in small concentration, and (2) that antibody (I think particularly IgG 7S antibody) is a potent feedback inhibiting the further production of IgM cells.

   The IgA situation is at a very interesting stage at present and I think you should say something of its special importance in transferring antibody to secretions like milk and saliva.

   My only general comment, after ten years' constant struggle with the implications of clonal selection theory, is the extreme heterogeneity, not only of antibody, but also of the experimental material. There are no experimental animals which have been fully studied for all the points relevant to immunological theory and it can be very difficult to try to build up a general picture from a mosaic of information about thymectomy from mice, delayed hypersensitivity from guinea-pigs, antibody structure from human myeloma proteins, and lymphocyte physiology from rats!

   I hope these notes may be of some interest.
   With best wishes,
   Yours sincerely,
    F. M. Burnet

P.S. In referring to my part in clonal selection theory, the key references are:
"The Clonal selection theory of acquired immunity" (1959), Cambridge University Press. (F. M. Burnet)
"A Darwinian approach to immunity," Nature, 203:451 (1964) (F. M. Burnet)
These should replace your reference 2.

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This page was established in Feb 2011 by Donald Forsdyke and was last edited 13 Nov 2020