Predisposed αβ T cell antigen receptor recognition of MHC and MHC-I like molecules?

•Recent insights, and surrounding controversy, into TCR ‘hard wiring’ is discussed.•An alternative hypothesis underpinning MHC-restriction is proposed.•Findings of TCR-MHC-I-like interactions are discussed.

The diverse αβ T cell receptor (TCR) repertoire exhibits versatility in its ability to generate antigen (Ag) receptors capable of interacting with polymorphic Major Histocompatibility Complex (MHC) molecules and monomorphic MHC-I like molecules, including the CD1 and MR1 families. Collectively, these evolutionarily related Ag-presenting molecules present peptides, lipids and vitamin B metabolites for T cell surveillance. Interestingly, whilst common TCR gene usage can underpin recognition of these distinct classes of Ags, it is unclear whether the ‘rules’ that govern αβTCR-Ag MHC interactions are shared. We highlight recent observations in the context of TCR biases towards MHC and MHC-I like molecules.