Immunologic Research

, Volume 64, Issue 4, pp 795–803 | Cite as

Dissecting the two models of TCR structure–function relationships

Interpretive Synthesis Review Article
First Online:

Abstract

There are only two comprehensive models attempting to account for the TCR structure–function relationships, referred to as the Standard or Centric model (Model I) and the Tritope model (Model II). This essay is written to analyze comparatively the two formulations of restrictive reactivity, stressing in particular the logic of each. Model I is essentially built on an analogy between the TCR and the BCR. Given a TCR with only one combining site (paratope), restrictive recognition requires that its ligand be viewed as a composite structure between the peptide and restricting element. It is this relationship that entrains a set of correlates that makes Model I untenable. Model II is predicated on the postulate that the recognition of the allele-specific determinants expressed by MHC-encoded restricting elements (R) is germline encoded and selected, whereas the recognition of peptide (P) is somatically encoded and selected. These selective pressures must operate on definable structures and this, in turn, necessitates a multiply recognitive T cell antigen receptor (TCR) with independent anti-R and anti-P paratopes that function coherently to signal restrictive reactivity. The consequences of this “two repertoire” postulate give us a concept of TCR structure quite distinct from that at present generally accepted, as well as a surprising relationship between numbers of functional TCR V gene segments and allele-specific determinants in the species. In the end, both models must deal with the relationship between the epitope–paratope interaction(s) and the signals to the T cell necessary for its differentiation and function.

Keywords

Thymus TCR function TCR signaling TCR differentiation Self–nonself discrimination TCR models 

Abbreviations

MHC

Major histocompatibility complex (it encodes many things beside R elements)

R

Restricting element, MHC-encoded

P

Peptide

RT

Thymic R responsible for positive selection

RA

Allogenic-R or allo-R

Q

The allele-specific interaction epitope formed between R and P. Often referred to as an “altered self” epitope or new antigenic determinant (NAD)

TCRVA

The V region of the alpha subunit of the TCR

TCRVB

The V region of the beta subunit of the TCR

oT

A T cell expressing a TCR prior to positive selection (CD4+CD8+)

iTh

Initial state T-helper, antigen-responsive cell after positive selection

eTh

Effector T-helper

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References

  1. 1.
    Langman RE, Cohn M. If the immune repertoire is large, random, and somatically generated, then…. Cell Immunol. 2002;216:15–22.CrossRefPubMedGoogle Scholar
  2. 2.
    Schumacher TNM, Ploegh HL. Are MHC-bound peptides a nuisance for positive selection? Immunity. 1994;1:721–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Cohn M. A stepwise model of polyreactivity of the T cell antigen-receptor (TCR): its impact on the self-nonself discrimination and on related observations (receptor editing, anergy, dual receptor cells). Cell Mol Life Sci. 2014;71:2033–45.CrossRefPubMedGoogle Scholar
  4. 4.
    Cohn M, Langman RE. The Protecton: the evolutionarily selected unit of humoral immunity. Immunol Rev. 1990;115:1–131.CrossRefGoogle Scholar
  5. 5.
    Cohn M, Langman RE, Mata J. A computerized model for the self-nonself discrimination at the level of the T-helper (Th-genesis). I. The origin of “primer” effector T-helpers. Int Immunol. 2002;14:1105–12.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Langman RE, Mata JJ, Cohn M. A computerized model for the self-nonself discrimination at the level of the T-helper (Th genesis) II. The behavior of the system upon encounter with nonself antigens. Int Immunol. 2003;15:593–609.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cohn M. On the logic of restrictive recognition of peptide by the T-cell antigen receptor. Immunol Res. 2011;50:49–68.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cohn M. Thoughts about positive selection in thymus. Scand J Immunol. 2016. doi: 10.1111/sji.12415.PubMedGoogle Scholar
  9. 9.
    Cohn M. “Allorestriction” should be distinguished from “alloreactivity”. Eur J Immunol. 2012;42:39–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Felix NJ, Allen PM. Specificity of T-cell alloreactivity. Nat Rev Immunol. 2007;7:942–53.CrossRefPubMedGoogle Scholar
  11. 11.
    Ashwell JD, Chen C, Schwartz RH. High frequency and nonrandom distribution of alloreactivity in T cell clones selected for recognition of foreign antigen in association with self class II molecules. J Immunol. 1986;136:389–95.PubMedGoogle Scholar
  12. 12.
    Langman RE, Cohn M. The Standard Model of T-cell receptor function: a critical reassessment. Scand J Immunol. 1999;49:570–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Müllbacher A, Lobigs M, Kos FJ, Langman RE. Alloreactive cytotoxic T-cell function, peptide nonspecific. Scand J Immunol. 1999;49:563–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Cohn M. Rationalizing thymic selection for functional T-cells: a commentary. Cell Immunol. 2015;298:83–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Wang J-h, Reinherz EL. Structural basis of T cell recognition of peptides bound to MHC molecules. Mol Immunol. 2001;38:1039–49.CrossRefGoogle Scholar
  16. 16.
    Garcia KC, Degano M, Speir JA, Wilson IA. Emerging principles for T cell receptor recognition of antigen in cellular immunity. Rev Immunogenet. 1999;1:75–90.PubMedGoogle Scholar
  17. 17.
    Garcia KC, Teyton L, Wilson IA. Structural basis of T cell recognition. Annu Rev Immunol. 1999;17:369–97.CrossRefPubMedGoogle Scholar
  18. 18.
    Reiser J-B, Grégoire C, Darnault C, Mosser T, Guimezanes A, Schmitt-Verhulst A-M, Fontecilla-Camps JC, Mazza G, Malissen B, Housset D. A T cell receptor CDR3b loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC Class I complex. Immunity. 2002;16:345–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Bakker TR, Anton van der Merwe P. Self-help in T cell recognition? Nat Immunol. 2002;3:11–2.CrossRefPubMedGoogle Scholar
  20. 20.
    Goldrath AW, Bevan MJ. Selecting and maintaining a diverse T-cell repertoire. Nature. 1999;402:255–62.CrossRefPubMedGoogle Scholar
  21. 21.
    Cohn M. A new concept of immune specificity emerges from a consideration of the Self-Nonself discrimination. Cell Immunol. 1997;181:103–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Langman RE. The specificity of immunological reactions. Mol Immunol. 2000;37:555–61.CrossRefPubMedGoogle Scholar
  23. 23.
    Matzinger P. Why positive selection? Immunol Rev. 1993;135:82–117.CrossRefGoogle Scholar
  24. 24.
    Cohn M. An alternative to current thinking about positive selection, negative selection and activation of T-cells. Immunology. 2004;111:1–6.CrossRefGoogle Scholar
  25. 25.
    Gil D, Schamel WA, Montoya M, Sánchez-Madrid F, Alarcón B. Recruitment of Nck by CD3e reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002;109:901–2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Conceptual Immunology GroupThe Salk InstituteLa JollaUSA

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