Alloreactivity: an old puzzle revisited.

Alloreactivity, defined as a strong primary T cell response against allelic variants of major histocompatibility complex (MHC) molecules in the species, has been a long-standing puzzle in immunology with some of its details remaining unclear up to now. Here I shall provide a historical overview of how our understanding of alloreactivity has evolved and propose an interpretation that considers alloreactivity to be a mixture of four mechanistically distinct prototypes of T cell response, namely, self-restricted peptide specific, allorestricted peptide specific, alloreactive peptide dependent and alloreactive peptide independent. The relative contribution of each prototype to a given alloresponse is dependent on the extent of disparity (i.e. the number and nature of amino acid substitutions in the docking surface for T cell receptor) between the MHC molecule that the T cell recognizes as self and the stimulating MHC molecule.