The molecular basis of allorecognition of major histocompatibility complex molecules by T lymphocytes

This review focuses on the response to foreign major histocompatibility complex (MHC) molecules by T lymphocytes. This phenomenon is characterized by a uniquely strong primary immune reaction, due to a very high precursor frequency of alloreactive T cells. This is manifest in vitro in the mixed lymphocyte reaction (MLR) and in vivo leads to allograft rejection and to graft versus host disease. Understanding this phenomenon requires an understanding of the nature of the ligand recognized by alloreactive T cells. In this review we report evidence in support of the two hypotheses which have been put forward to account for the high precursor frequency of anti-MHC alloreactive T cells. The high determinant hypothesis emphasized the implication of direct contact between the T cell receptor and the MHC molecule; the multiple binary complex hypothesis envisages that alloreactive T cells are specific for self peptide bound by the foreign MHC molecule. With these two lines of apparently contradictory evidence in mind we propose two distinct models to account for the phenomenon of allorecognition and to accommodate it within a self-MHC-restricted T cell repertoire. Which model is most applicable to a particular alloresponse is largely determined by the structural relationship between the responder and the stimulator MHC molecules.