The Tritope Model for restrictive recognition of antigen by T-cells

Abstract

Based on the Tritope model of the TCR (Cohn, 2005c), a set of functional and evolutionary problems surrounding restrictive recognition of antigen are discussed. These include the origin of allelespecific recognition, the selection pressures for polygeneism and polymorphism, the TCR signaling interactions, the centrality of effector T-helper (eTh)-dependence for activation, the role of haplotype exclusion, "nonclassical" MHC-elements, alloreactivity versus xenoreactivity, etc. Further, a set of observations believed to support the Standard Model are reinterpreted.A previous paper (Cohn, 2005c) detailed a new model (referred to as the Tritope Model) of the T-cell antigen-receptor (TCR) and analyzed its effectiveness in dealing with three basic phenomena, restrictive recognition, positive selection and allorecognition. The reasons for developing a model competing with the Standard Model have been discussed (Cohn, 2003;Cohn, 2004a;Cohn, 2004b;Cohn, 2006a;Langman and Cohn, 1999). Here we will extend the analysis of the Tritope Model by considering a set of phenomena related to the genetics, ontogeny and evolution of the TCR-MHC system. Further, the steps in the Self (S)-Nonself (NS) discrimination that are affected by the Tritope Model will be analyzed. Recalling the Tritope Model (Cohn, 2005c)The TCR encodes two distinctly different repertoires. One is germline-selected to recognize the allele-specific determinants (a) on the MHC-encoded restricting elements (R) of the species; the other is a somatically generated random repertoire that recognizes peptide (P) bound to the restricting element (R) as [PR].In order to map the two repertoires onto the TCR structure it was argued that (see List of Abbreviations):1. Single V-gene segments, Vα or Vβ, encode recognition of the allele-specific determinants (a). 2.Each domain (RI) or subunit (RII) of the R-element expresses an allele-specific determinant (a) (i.e., 2a per R).3. Peptide (P) is recognized by an anti-P site on the TCR formed by complementation of the CDR3 junctional regions of the α and β subunits.

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

“…This distinction explains the findings of Felix et al (2007) as discussed in detail elsewhere (Cohn, 2008a;Cohn, 2008b). In their investigation, a selected set of hybridomas restricted to A b were shown to respond to E k in a peptide-dependent manner implying that A b and E k share an allele-specific determinant (allorestriction).…”

“…As Feng et al (2007) were unaware of the existence of the Tritope Model (Cohn, 2003;Cohn, 2005;Cohn, 2007;Cohn, 2008b;Langman and Cohn, 1999), the fact that they come to similar conclusions based on structural arguments is, therefore, very reassuring. However, the remark that "immunological observations give credence to the idea of a 'primordial' affinity between TCR and MHC driven by conserved sets of germline-encoded elements, which are then modulated by the MHC-bound peptide" illustrates how deeply entrenched in their thinking is the Standard (or interaction antigen) Model (Langman and Cohn, 1999) that paradoxically their data clearly contradicts.…”

“…This explains the failure of Portoles et al (1989) to observe alloreactivity by D10 TCR for A u . The Tritope Model faces the problem of a requirement for recognition of an a-site in order to signal from either of the two orientations (Cohn, 2003;Cohn, 2004;Cohn, 2005;Cohn, 2007;Cohn, 2008b;Langman and Cohn, 1999).…”

“…Theories are there to fail. While every paper describing the Tritope Model (Cohn, 2003;Cohn, 2004;Cohn, 2005;Cohn, 2008a;Cohn, 2008b) has included such critical experiments, the community of supporters of the Standard, Interaction or Slip and Slide Centric Model have yet to face this requirement.…”

“…The consequence of this is that the total number of restricting allele-specific determinants of the species must be less than the number of functional V-genes, Vα + Vβ, acting as a single pool (Cohn, 2008b;Langman and Cohn, 1999). In mouse, there are roughly 80 Vα and 20 Vβ gene-segments, a proportion of which are nonfunctional or redundant (i.e., ≥2 distinguishable V domains that recognize the same allele-specific determinant).…”