T cells are key effectors of the adaptive immune response, with a number of important roles in the elimination of pathogens. They are also major effectors in autoimmune diseases and, therefore, there is an important need to understand how they are activated and regulated. Engagement of antigen-specific T cell receptors (TCRs) is a prerequisite for T cell activation. Acquisition of appropriate effector T cell function requires the participation of multiple signals from the T cell microenvironment. Activation of T cells occurs upon ligation of clonotypic T cell receptors (TCRs) by MHC molecules on antigen-presenting cells (APCs) presenting peptides (peptide–MHC) from either endogenously encoded self molecules or exogenously encoded pathogen molecules.[1]