Adaptive T cell tuning in immune regulation and immunotherapy of autoimmune diseases

•The immune cell repertoire is controlled through T cell receptor and costimulatory molecule dependant selection of CD4+ and Foxp3+ T cells in the thymus.•The immune response to antigen is fine-tuned through activation induced cell death.•Chronic exposure to antigen leads to desensitization of immune responses through anergy and the generation of regulatory type 1 responses.•Differentiation of anergic Tr1 cells arises from radically reduced cell signalling and epigenetic priming of tolerance associated genes.•Autoimmune responses are successfully controlled by chronic exposure to antigen processing independent T cell epitopes. Lymphocyte receptors confer antigen specificity on the adaptive immune response. Increasing evidence points to the role of adaptive tuning particularly amongst CD4+ T cell responses. This review summarises how T cell tuning impacts on critically important aspects of immune regulation including thymic selection, the immune response to chronic antigen exposure and antigen-specific immunotherapy of autoimmune conditions. Recent work has revealed a novel mechanism for T cell anergy and regulatory type 1 T cell differentiation through a limitation of T cell receptor mediated signalling combined with epigenetic priming of tolerance associated genes.