A Disquisition on MHC Restriction and T Cell Recognition in Five Acts

The seminal discovery in the early 1970s, credited to Peter Doherty and Rolf Zinkernagel, of major histocompatibility complex (MHC) restriction exhibited by cytotoxic T cells represented a major conceptual advance in understanding antigen recognition by conventional T cells. This advance also led to other major new insights into the ontogeny and immunobiology of T cells and catalyzed a renaissance in viral immunology. In this commentary in honor of Peter Doherty, I offer five brief reflections on different aspects of the phenomenon of MHC restriction and the process by which it was discovered and explained. In the first of these sections, I offer a reinterpretation of MHC restriction that reframes the constraints on self-MHC recognition in terms of the probabilities of recognizing a given nominal antigen peptide in the context of an MHC molecule that is nonself on the basis of differing in amino acid sequence from the self-restriction element at one or more positions. Subsequent sections address: (i) the ways in which general ideas, developed subsequent to the discovery of MHC restriction, about the intricacies of antigen recognition by antibodies apply to T cell receptors binding to MHC/peptide complexes; (ii) how to reconcile the existence of MHC restriction with the impressive magnitude of T cell responses to nonself MHC antigens; (iii) the possible relevance to MHC restriction and immune system function of ideas from mathematical logic that relate to the consequences of self-reference; and (iv) the implications for the philosophy of science of MHC restriction and the processes of its discovery and acceptance within the immunology research community.