Reconciling views on T cell receptor germline bias for MHC

Whether MHC restriction by the T cell receptor (TCR) is a product of evolutionary pressures leading to germline-encoded ‘rules of engagement’ remains avidly debated. Structural results derived from analysis of TCR−peptide–MHC complexes appear to support a model of physical specificity between TCR germline V regions and MHC. Yet, some recent evidence suggests that thymic selection, and co-receptors may have misled us into thinking the TCR is exclusively MHC-specific, when in fact, TCRs can robustly engage non-MHC ligands when given the chance. Here, I propose that seemingly contradictory data and hypotheses for, and against, germline bias are, in fact, compatible and can be reconciled into a unifying model.