Thymic Origins of T Cell Receptor Alloreactivity

Major histocompatibility complex (MHC) restriction is a unique feature of T cell antigen recognition. Mature T cells respond to antigenic nonself peptides bound to self-MHC molecules, but a sizeable fraction of peripheral T cells can also respond to nonself peptide-MHC (pMHC) complexes in the context of transplantation. MHC specificity of the T cell receptor (TCR) repertoire is shaped during thymic development. Two hypotheses have been proposed to explain MHC specificity of T cells. It has been suggested that MHC specificity is an intrinsic feature of TCR structure, mediated by the germline-encoded regions of the TCR sequence. In support of this model, an estimated 15% to 30% of preselection TCR repertoire is estimated to be MHC-specific. Moreover, structural studies have shown some degree of conserved binding topology for TCR-peptide MHC complexes. However, there is also evidence that MHC restriction can be imposed on the TCR repertoire during thymic development, and it has been proposed that the interaction of the Lck kinase with CD4 or CD8 coreceptors is critical for generation of MHC specificity. This review will discuss recent work on assessment of the preselection of TCR repertoire, molecular evidence for the germline encoded TCR bias for MHC, and for the coreceptor sequestration model in the context of alloreactivity and transplantation.