Review

“Altered-self” or “near-self” in the positive selection of lymphocyte repertoires?
Donald R. Forsdyke
Immunology Letters (2005) 100, 103-106  
Received 23 March 2005; accepted 30 March 2005; Available online at publisher's website 29 April 2005
Copyright Elsevier

Abstract

Positive selection of lymphocyte repertoires is now recognized as applying to both B and T cells. However, much of the early literature on positive selection focussed on cell-mediated immunity (T cells), which biased consideration of its general biological role. The term “altered-self,” which initially captured the idea of self (i.e. MHC) altered by the addition of what was later found to be a peptide fragment, has not proven robust and may now be clouding our understanding. It is recommended that the term “near-self” be reintroduced since it captures the essence of the probable underlying adaptive process –  sub-threshold self-reactivity to countermand rapid pathogen mutation.

Contents

1. Ideas that soar

2. Progressive pathogen evolution countermanded by stiffened host defences 

3. Focus on T cells and MHC

4. Biological role sought

5. Small “holes” in repertoire allow hidden “self” to be reinterpreted as “not-self”

6. Homeostatic regulation of educated populations 

7. Conclusion 

References 

End Note 2005

End_Note_2012_

End_Note_May_2014_

 

1. Ideas that soar

Some ideas crawl, some run, some fly; and in this case words are the wings they fly with.” Thus, Samuel Butler [1] 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 [2]. The words Williams assigned to the idea of the selfish gene, lost to the “selfish gene” of Dawkins [3]. 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. 

2. 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” [11]. 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 [11].

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[33] that "both the mature, naïve T cell repertoire and the mature, naïve 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

The 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 Kearney [32] point to the great importance of “subthreshold reactivity,” while noting “that positive selection is a critical feature in the establishment and maintenance of all lymphocyte pools.” The early failure generally to perceive that positive selection also applied to B cells is held to have been “keenly influenced by the appreciation of MHC restriction,” which diverted attention to T cells. 
      To the rhetorical question, “What is the goal of continuous self-orientated positive selection?”, Cancro and Kearney [32] reply that “the potential of microbes for rapid genetic variation and consequent immune evasion requires a means to prospectively evaluate probable protective utility.” This, they suggest, means that “the more comprehensive and avid the array of subthreshold self-reactivity, the smaller the unaccounted structural space between self and non-self, and the lower the probability of immune evasion.” Thus: “An attractive consequence of this model is the visualization of positive selection as an ongoing, dynamic repertoire refinement process, whereby clonal survival – regardless of functional maturity – is tied to maximal subthreshold self-reactivity, such that potential protective value is continuously reassessed relative to competitor clones.”
      While Cancro and Kearney do not expand on “subthreshhold self-reactivity” (i.e. near-self reactivity), or “unaccounted structural space between self and non-self” (i.e. “holes” in repertoires), they appear to be reiterating an important aspect of the original affinity/avidity maturation model for positive selection [11, 35-37].

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 [38], 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 [39]. 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].

6. 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 [11]. In the case of B cells the levels of the corresponding natural antibodies (IgM) would fluctuate similarly [46, 47].
      Thus, positive selection in what Jerne [12] called a “mutant-breeding” organ (e.g. thymus in the case of T cells and some B cells [48]), generates sets of lymphocytes with the potential to respond, albeit weakly, to various self-determinants. Negative selection often eliminates cells with the potential to respond to self with high specificity. Final immunological repertoires consist of numerous small clones of cells. Members of a particular clone are capable of recognizing a particular set of
near-self antigenic determinants. The range of specific responsiveness exhibited by an individual reflects the outcome of negative and positive selections of lymphocytes (and further selections by emerging antigens) over many years.
      To renew such “educated” lymphocyte populations after depletion (perhaps due to haemorrhage), could be a protracted process if renewal required reeducation. Thus, educated cells should be more immediately responsive to homeostatic control mechanisms affecting the size of lymphocyte populations than “uneducated” stem cells. Peripheral immunologically-competent clones should be responsive not only to the cues provided by antigenic determinants (through the determinant-specific lymphocyte antigen receptor) but also to cues provided by growth factors concerned with lymphocyte population size homeostasis (through appropriate receptors). In addition to the latter growth factors, self-antigens have a role not only to select a receptor repertoire, but also to keep naïve cells “alive and 'ready for action' in the periphery” [28].

  7. Conclusion

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.” 

References

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End Note 2005

The author's 1975 paper in the Journal of Theoretical Biology  (11) was informed by his extensive focus on dose-response relationships in lymphocyte cultures over the prior decade. These involved varying doses both of polyclonal mitogens (lectins) and oligoclonal mitogens (specific antigens). Key findings were that serum antibody and lectin-binding factors buffered target cells against reaction with antigen and lectin, respectively, and that dose-response curves showed inhibition at high concentrations that in certain circumstances was complement-dependent. Click Here

End Note 2012

Speiser et al. (2008) have noted that "altered" antigens are less effective than "natural" self antigens in triggering tumour-reactive CD8 lymphocytes.

Speiser et al. (2008) Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc. Natl. Acad. Sci. USA 105, 3849-3854.

End Note May 2014

My puzzlement at the "absence of knowledge" postulate of Mandl et al. (2013) that I commented on elsewhere in these pages (Click Here), was rekindled by their further commentary (Mandl & Germain 2014) on the technically exquisite paper of  Birnbaum et al. (2014). All authors accept as given that there is an enormous spectrum of peptides that the organism is helpless to anticipate. Two example quotations:

"Indeed, given that the calculated diversity of potential peptide antigens is much larger than TCR repertoire diversity, TCR cross-reactivity appears to be a biological imperative" (Birnbaum et al, 2014).

"A TCR repertoire ... is several magnitudes less diverse than the total set of peptides that are presented by MHC molecules ... . Hence, a necessary feature of a TCR repertoire is that a T cell is able to recognize and respond to many peptides" (Mandl & Germain, 2014).

But, as set out above, positive repertoire selection occurs in order to focus on a greatly shrunken universe of foreign peptides, which are derived from rapidly mutating microorganisms that have aimed to exploit "holes" in the lymphocyte repertoire by mutating progressively closer to host-self. Thus, the lymphocyte repertoire is set to consider "near-self," and receptor degeneracy is not a strict requirement. This is precisely what Birnbaum et al. (2014) reported.

That the repertoire is biased by positive selection towards "near-self" was a logical deduction from the postulate that microorganisms would try to exploit the holes (Forsdyke 1975). Evidence for such holes is growing (Calis, de Boer & Kesmir 2012).

Birnbaum, Mendoza, Sethi, Dong, Glanville, Dobbins, Ozkan, Davis, Wucherpfennig, Garcia (2014). Cell 157, 1073–1087. Deconstructing the Peptide-MHC Specificity of T Cell Recognition.

Calis JJA, de Boer RJ, Kesmir C (2012) PLOS Computational Biology 8, e1002412. Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire.

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.

Mandl JN, Germain RN. (2014) Cell 157, 1006-1008. Focusing on T cell cross-reactivity.



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Posted May 2005 and last edited 26 May 2014 by Donald Forsdyke