Revealing the TCR bias for MHC molecules

Adaptive immunity has long been considered the hallmark trait associated with jawed vertebrates. Although unconventional forms of adaptive immunity, such as variable lymphocyte receptors in lampreys (1) and CRISPR/Cas in bacteria (2), have recently gained recognition, somatic recombination generating unique antigen receptors provides diversity unparalleled by other forms of immunity. On T cells, the T-cell antigen receptor (TCR) is one such receptor comprising α- and β-polypeptide chains (each of which is produced via DNA recombination), which together provide a combinatorial diversity estimated to exceed potentially 1015 different receptors (3). As T cells develop and mature in the thymus, they undergo a process called selection, which grooms them for mounting appropriate immune responses upon future antigen exposures in peripheral tissues. Intriguingly, the vast majority of TCRs recognize linear peptides bound to MHC molecules during both development and immune responses (4, 5). Upon first identifying this phenomenon of MHC-restriction, investigators were immediately prompted to study and understand the molecular basis underlying this bias (4⇓–6). Do TCRs bear regions in their protein structures to bias their interaction with MHC and make the selection process more efficient? Or are TCRs inherently polyspecific and it is the process of selection that forces their specificity for MHC? Despite years of work exploring reasons for this predisposition, a clear consensus remains elusive. In PNAS, Parrish et al., using a sensitive in vitro system, provide new evidence to suggest that TCRs possess an inherent bias to recognize MHC molecules (7). Forty-five years have passed since Niels Jerne proposed the hypothesis that TCR molecules might have undergone coevolution with histocompatibility molecules (8). Since then, a number of studies have supported this idea. Recently, when the Bendelac group decided to pair unselected TCRα chains with random TCRβ chains in vivo, they observed that 15% …