or "near-self" in the positive selection of lymphocyte repertoires?
Ideas that soar
"Some ideas crawl, some run, some fly; and in this case words are the wings they fly with." Thus, Samuel Butler  reminded us that ideas usually first arrive, just as ideas. The words they subsequently fly with can aid in their comprehension. But different words compete for this role. The words Talmage assigned to the idea of clonal selection in immunity, lost to the "clonal selection" of Burnet . The words Williams assigned to the idea of the selfish gene, lost to the "selfish gene" of Dawkins . These latter assignments have endured. However, as ideas evolve, early winners may be seen as, not merely anachronistic, but actively misleading. If ideas are to soar, sometimes reassignation becomes imperative. I propose here that such a reassignation is long overdue in the case of some words associated with the idea of positive selection of lymphocyte repertoires.
Progressive pathogen evolution countermanded by stiffened host defences
The generation of repertoires of immunologically competent cells involves
both negative and positive
selection of lymphocytes. The need for negative selection of
cells with the potential to attack an organism's own tissues has been long
appreciated [2, 4]. In its extreme form, negative selection destroys potentially
self-reactive lymphocytes, often by apoptosis [5, 6], but possibly also by
complement-dependent processes [2, 7-10].
Why positive selection? Whatever the form and mechanism of negative selection, "holes" are generated in lymphocyte repertoires that pathogens might exploit. To the extent that the negative selection of lymphocytes with the potential to respond against self antigenic determinants had occurred, a pathogenic microbe that could, in one step, mutate one of its antigenic determinants 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 antigenic determinant. However, mutation is generally a stepwise process. If a microbe, by mutating a step towards self along the path from not-self to self, secured a selective advantage, then the mutant form would come to dominate the 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 could become progressively better adapted - often 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 progressively closer to host-self, the microbe encountered progressively stiffer host immune 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" . To emphasize this proximity to self, positive selection was initially described as the generation of repertoires of potential immunologically competent cells that would have been preselected to respond against "near-self" antigenic determinants. Furthermore, there seemed no reason to doubt that this preselection would apply generically to both B and T lymphocytes .
3. Focus on T cells and MHC
The possibility of a relationship
between positive selection and major histocompatability complex (MHC) antigens
was introduced, but then dismissed, by Jerne in 1971, since no adaptive
mechanism could be inferred [12-14]. The concept of positive selection in the
context of near-self,
when introduced in 1975 [8, 11, 15], implicated MHC antigens indirectly
[16, 17]. Much of the early literature on positive selection was
concerned with MHC-restricted antigen recognition by T cells, and the
term "altered-self", introduced in 1974, won wide acceptance in this context
since it captured the idea of self (i.e. MHC) altered
by the addition of a (perhaps foreign) peptide fragment [18, 19]. However, the
more recent literature has come to recognize positive selection as applying
generically to both T and B cells, and at various stages of development [20-32].
Janeway, for example, concluded in 2001 that "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."
4. Biological role sought
term "altered-self" fails to capture the essence of the probable general
mechanism for the positive selection of B and T cells at various stages of
development as advanced in 1975 [11, 34]. This is not because the mechanism
remains unrecognized. Seeking "the underlying biological rationale for this
process," Cancro and
5. Small "holes" in repertoire allow hidden "self" to be reinterpreted as "not-self"
Thus, it is here suggested that future considerations of positive selection return to "near-self" and discard "altered-self" as anachronistic. "Near-self" better reflects the likely underlying mechanism, which should, in principle, apply generically to all lymphocyte subsets that emerge from repertoire filters. It should also be noted that evolutionary selective forces have determined that "holes" in lymphocyte repertoires - the "windows of opportunity" for prospective pathogens - are small. Notwithstanding the "promiscuous" expression of some self-antigens centrally , many potential self-antigens are hidden within cells and so should not participate in the moulding ("skewing") of lymphocyte repertoires. Repertoire "holes" are smaller because these hidden self-antigens have not declared their presence. Indeed, it is these self-antigens, reinterpreted as "not-self" by cancer cells, which are often targeted by tumour-specific lymphocytes. There is an on-going refinement of what is deemed "not-self" by cellular mechanisms that are considered elsewhere . Immune responses to "not-self" cancer cells are usually neither cancer-specific, nor cancer-type-specific. Rather, they address polymorphic, individual-specific, antigenic determinants [40-43].
Homeostatic regulation of educated populations
It is now clear that active homeostatic mechanisms operating on
lymphocyte subpopulations would tend to keep total population sizes constant
[44, 45]. Hence, when cells of low specificity for a particular antigenic
determinant increase in number, the number of cells of higher and even lower
specificities would decrease in a calibrated fashion. Since the majority of
cells in the total population are of zero and very low specificities, the
absolute decrease would mainly affect these cell types . In the case of B
cells the levels of the corresponding natural antibodies (IgM) would fluctuate
similarly [46, 47].
When positive selection was seen as exclusive to T cells the term "altered-self" had a certain utility, and "near-self" lost out. Now that the generic nature of positive selection is recognized, "altered-self" appears out-dated and should be replaced with a term that most likely captures the underlying mechanism - "near self."
 Butler S.
Thought and language. In: The Humour of
Homer and Other Essays.
 Burnet F M. The
Clonal Selection Theory of Acquired Immunity.
 Dawkins R. The
 Ehrlich P. On
immunity with special reference to cell life. Proc R Soc Lond
 Liblau RL, Tisch R, Shokat K, Yang X-D, Dumont N, Goodnow CC, McDevitt HO. Intravenous injection of soluble antigen induces thymic and peripheral T-cell apoptosis. Proc. Natl. Acad. Sci. USA 1996;93:3031-3036.
 Monroe J G. Molecular mechanisms regulating B-cell negative selection. Biochem Soc Trans 1997;25:643-647.
 Azar MM, Good RA. The inhibitory effect of vitamin A on complement levels and tolerance induction. J Immunol 1971;106:241-245.
 Forsdyke DR. Serum factors affecting the incorporation of [3H]thymidine by lymphocytes stimulated by antigen. II. Evidence for a role of complement from studies with heated serum. Immunol 1973;25:597-612.
 Carroll MC. The role of complement in B cell activation and tolerance. Adv Immunol 2000;74:61-88.
 Manderson AP, Botto M, Walport MJ. The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 2004;22:431-456.
 Jerne NK. The somatic generation of immune regulation. Eur J Immunol 1971;1:1-9.
 Forsdyke DR. Jerne and positive selection. Immunol
 Huseby E, Kappler J, Marrack P. TCR-MHC/peptide interactions: kissing-cousins or a shotgut wedding. Eur J Immunol 2004;34:1243-1250.
 Forsdyke DR. Serum factors affecting the incorporation of [3H]thymidine by lymphocytes stimulated by antigen. 1. Serum concentration. Immunol 1973;25:583-595.
 Bodmer WF. Evolutionary significance of the HLA system. Nature 1972;237:139-145.
 Benecerraf B, McDevitt H0. Histocompatibility-linked immune response genes. Science 1972;175:273-279.
 Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 1974;248:701-702.
 Zinkernagel RM, Doherty PC. The discovery of MHC restriction. Immunol Today 1997;18:14-17.
 von Boehmer, H. Positive selection of lymphocytes. Cell 1994;76:219-228.
 Schwartz RS, Stollar BD. Heavy-chain directed B-cell maturation: continuous clonal selection beginning at the pre-B cell stage. Immunol Today 1994;15:27-32.
 Minnerath JM, Mueller CM, Buron S, Jemmerson R. B lymphocyte recognition of cytochrome c: higher frequency of cells specific for self versus foreign antigen early in the immune response and V gene usage in the response to self antigen. Eur J Immunol 1995;25:784-791.
 Neuberger MS. Antigen receptor signalling gives lymphocytes a long life. Cell 1997;90:971-973.
 Cyster JG, Healy JI, Kishihara K, Mak TW, Thomas ML, Goodnow CC. Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 1996;381:325-328.
 Hachemi-Rachedi S, Cumano A, Drapier A-M, Cazenave P-A, Sanchez P. Does positive selection determine the B cell repertoire? Eur J Immunol 1997;27:1069-1074.
 Hayakawa K, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, Silver J, Hardy RR. Positive selection of natural autoreactive B cells. Science 1999;285:113-116.
 Townsend SE, Weintraub BC. Goodnow CC. Growing up on the streets: why B-cell development differs from T-cell development. Immunol Today 1999;20:217-220.
 Goldrath AW, Bevan MJ. Selecting and maintaining a diverse T-cell repertoire. Nature 1999;402:255-262.
 Ernst B, Lee D-S, Chang JM, Sprent J, Surh CD. The
peptide ligands mediating positive selection in the thymus control T cell
survival and homeostatic proliferation in the periphery. Immunity
 Wang H, Clarke SH. Evidence for a ligand-mediated
positive selection signal in differentiation to a mature B cell. J Immunol
 Gaudin E, Hao Y, Rosado MM, Chaby R, Girard R, Freitas AA. Positive selection of B cells expressing low densities of self-reactive BCRs. J Exp Med 2004;199:843-853.
 Cancro MP,
 Janeway CA. How the immune system works to protect the host from infection: a personal view. Proc Natl Acad Sci USA 2001;98:7461-7468.
 Sprent J, Webb SR. Function and specificity of T
cell subsets in the mouse. Adv Immunol
 Ashton-Rickardt PG, Tonegawa S. A differential-avidity model for T-cell selection. Immunol Today 1994;15:362-366.
 Detours V,
 Kyewski B, Derbinski J. Self-representation in the thymus: an extended view. Nature Rev Immunol 2004;4:688-698.
 Gleimer M, Parham P. Stress management: MHC class 1 and class 1-like molecules as reporters of cellular stress. Immunity 2003;19:469-477.
 Spierings E, Wieles B, Goulmy E. Minor histocompatability antigens - big in tumour therapy. Trends Immunol 2004;25:56-60.
 Tanchot C, Fernandes HV, Rocha B. The organization of mature T-cell pools. Phil Trans R Soc Lond B 2000;355;323-328.
 Troy AE, Shen H. Homeostatic proliferation of peripheral T lymphocytes is regulated by clonal competition. J Immunol 2003;170:672-676.
 Nobrega A, Stransky B, Nicolas N, Coutinho A. (2002) Regeneration of natural antibody repertoire after massive ablation of lymphoid system: robust selection mechanisms preserve antigen binding specificities. J Immunol 2002;169:2971-2978.
 Wardemann H, Yurasov S, Schaefer A, Young J, Meffre E, Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science 2003;301:1374-1377.
Next: For Intracellular Self/Not-self Discrimination (Click Here)
Return to: Theoretical Immunology Index (Click Here)
Return to: HomePage (Click Here)
Posted May 2005 and last edited 13 Nov 2020 by Donald Forsdyke