Dissecting the two models of TCR structure-function relationships.
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.
Conceptual Immunology Group, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA. cohn@salk.edu.
Melvin
0000-0003-0191-0260
M
Cohn
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D006680:HLA Antigens / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000378:metabolism; D006801:Humans; D018448:Models, Immunological; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism; D017634:Self Tolerance; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens; D006680:HLA Antigens; D006649:Histocompatibility Antigens; D010455:Peptides; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell
Self–nonself discrimination; TCR differentiation; TCR function; TCR models; TCR signaling; Thymus