T-cell allorecognition: a case of mistaken identity or déjà vu?

T cells bearing αβ T-cell receptors (TCRs) are selected by a subset of peptide-laden major histocompatibility (pMHC) molecules in the thymus and in the periphery and therefore are restricted to recognising host or ‘self’ MHC molecules. Nevertheless, T cells are inherently cross-reactive and often react with ‘foreign’ allogeneic MHC molecules (direct T-cell alloreactivity), manifested clinically as organ transplant rejection. Although the basis of T-cell alloreactivity has remained a puzzle to immunologists for decades, studies on alloreactive TCRs have begun to shed light on the basic mechanisms underpinning this ‘mistaken identity’. Here we review recent advances in the field, focusing on structural and cellular studies, showing that alloreactivity may sometimes result from cross-reactivity without molecular mimicry and at other times may result directly from TCR interactions with allogeneic pMHC surfaces that mimic the cognate ligand.