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.