Role of conserved MHC residues for interaction with T cell antigen receptors, The

Abstract

The interaction of αβT cell antigen receptors (TCRs) with peptides in the context of major histocompatibility complex (MHC) molecules lies at the center of adaptive immunity. Whether the TCRs evolutionary bias guides this specificity, or, rather, processes in the thymus, involving co-receptors and other molecules, select an MHC specific repertoire de novo from a random repertoire, is a longstanding immunological question. Here, using nuclease targeted mutagenesis, I address this question in vivo by generating three independent lines of knock-in mice with single point mutations of conserved class II MHC amino acids that are often involved in interactions with the germline encoded portions of TCRs. While the TCR repertoire generated in these mutants is similar in size and diversity to wild-type (WT) mice, the evolutionary bias of TCRs for MHC is seen in the shift and preferential usage of some TCR subfamilies over others. Furthermore, the T cells educated on these mutant MHC molecules demonstrate alloreactivity to each other and WT mice, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection as well as the evolutionary bias of TCRs for MHC.