Generation and characterization of αβTCRs that recognize MHC-independent ligands

MHC-restriction is the unique feature of T cell antigen recognition, but its basis remains controversial. Currently, MHC-specificity is thought to be germline-encoded. That conclusion was based on structural analyses of αβT cell antigen receptors (αβTCRs) from T cells that had undergone MHC-specific thymic selection. Here, for the first time, αβTCRs from T cells that have not undergone MHC-specific thymic selection are analyzed. In contrast to conventional pMHC-specific αβTCRs, receptors that underwent thymic selection in the absence of MHC resemble antibodies in recognizing glycosylation-dependent conformational epitopes on a native self-protein, CD155, with high affinity and independently of MHC. Furthermore, CD155 recognition is mediated by the αβTCR combining site and involves specific CDR2-encoded amino acids previously thought to uniquely impose MHC specificity, contradicting the fundamental premise of the germline concept. Therefore, in the absence of MHC-specific thymic selection, αβTCRs resemble antibodies in recognizing conformational epitopes on MHC-independent ligands, revealing that MHC-specificity is not an intrinsic property of all αβTCRs