a | T cell activation begins with interaction of the T cell receptor (TCR) on a T cell with major histocompatibility complex (MHC) bound to antigen on an antigen-presenting cell (APC). This is known as signal 1, but appropriate activation of the T cell requires additional signals that are provided by the interaction between CD28 and B7 (signal 2). b | T cell activation is limited by cytotoxic T lymphocyte-associated protein 4 (CTLA4), which is upregulated on activated T cells, where it outcompetes CD28 for binding to B7 on an APC. Additional regulation of T cell activity is also provided by later inhibitory signals through other molecules such as programmed cell death 1 (PD1), which binds to PD1 ligand 1 (PDL1). Other regulators of T cell activation have recently been characterized and may have important roles; these regulators include T cell immunoglobulin and mucin domain-containing protein 3 (TIM3; also known as HAVCR2) and V-domain immunoglobulin suppressor of T cell activation (VISTA)60,61.