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

T cells bearing alphabeta 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.