What does the T-cell receptor recognize when it docks on an MHC-encoded restricting element?

Abstract

The postulate is analyzed that single V-gene segments encode recognition of the allele-specific determinants (a) required for the restrictive response of the αβTCR to peptide. The consequence of this is that the positively selected V-domain, Vα or Vβ, engages an allele-specific determinant (a) on one subunit or domain of the MHC-encoded restricting element. The entrained V-domain docks on an invariant determinant (i) on the complementing subunit or domain. Consequently, each functional V-domain expresses an anti-a site and an anti-i site, and all subunits or domains of MHCencoded restricting elements express an a-and i-determinant.The evidence, both biological and structural, discussed here strongly support this postulate which has far reaching consequences.The goal of this commentary is to analyze the data that are necessary and sufficient to establish a postulate of the Tritope Model, namely that the V-gene segments, Vα and Vβ, act as an single pool specifying recognition of the allele-specific determinants expressed on the MHC-encoded restricting elements of the species. Aspects of this postulate will also be discussed.This version was revised to incorporate the criticisms of reviewers who also requested that I discuss additional data. As a compromise, those data which are believed to be incompatible with my argument, are analyzed.

On the logic of restrictive recognition of peptide by the T-cell antigen receptor

“…This finding (discussed in detail in Ref. [73]) of a docking site common to ${\mathrm{normalA}}_{\alpha }^{\mathrm{normalk}}$ and ${\mathrm{normalA}}_{\alpha }^{\mathrm{normalu}}$ favors the assumption that the “interaction codon” is the structure defining the allele-specific determinant shared by ${\mathrm{normalA}}_{\alpha }^{\mathrm{normalk}}$ and ${\mathrm{normalA}}_{\alpha }^{\mathrm{normalu}}$. The cited study of Hong et al [43] (Table 1) supports this assumption that the interaction codon is an a-site , not an i-site , on ${\mathrm{normalA}}_{\alpha }^{\mathrm{normalu}}/{\mathrm{normalA}}_{\alpha }^{\mathrm{normalk}}$…”

Challenging The Tritope Model of T cell Receptor Structure–Function Relationships with Classical Data on ‘Super’ and ‘Allo‐MHC’ Antigens

“…What is crucial is that these two assays define the same alleles (restriction epitopes), a fact explained expressly and uniquely by the Tritope Model. Germline selection for the recognition of R by the TCR is revealed by evolutionary genetics; molecular morphology tells us what are the structural targets of the germline selection once its existence is established [33].…”

On Recognizing ‘Shades‐of‐Gray’ (Self–Nonself Discrimination) or ‘Colour’ (Integrity Model) by The Immune System

“…When comparing the S‐NS discrimination and Danger models of the function of the immune system, here are the differences according to the shades‐of‐gray comparison. As I suggested earlier, I view the S‐NS discrimination as an oversimplification, because it fails to see colours of the antigenic world (Fig.…”

“…This is an updated model based on previous reports [1,2,4]. [6][7][8]15]. The argument introduces different orientations of the TCR docking on peptide-MHC (pMHC) that is well documented, and it could provide the basis for understanding individual differences observed in frequencies of various TCR variable regions (as illustrated by their differences in MHC congenic mouse stains in his article presented in this issue) [9].…”

“…Namely, Cohn believes that two chains can yield two different signals, whereas the Standard model sees TCR as a single‐receptor signalling unit . Cohn plausibly discusses how peptide recognition could have been incorporated in the positive selection process and explains it such that only certain preferential combinations (of TCR chains) would work well, leaving other pairings non‐viable . The argument introduces different orientations of the TCR docking on peptide–MHC (pMHC) that is well documented, and it could provide the basis for understanding individual differences observed in frequencies of various TCR variable regions (as illustrated by their differences in MHC congenic mouse stains in his article presented in this issue) .…”