Tailoring T-cell receptor signals by proximal negative feedback mechanisms

Key Points T-cell receptor (TCR) signalling is central for the fundamental choice between immunity and tolerance and for regulating T-cell differentiation after exposure to antigen. Signalling circuits control these events by negative and positive mechanisms. The machinery that governs TCR signalling, also known as the TCR signalosome, is composed of three modules that regulate SRC-family protein tyrosine kinases, signal triggering following ligation of the TCR with peptide–MHC complexes and signal diversification for activation of numerous downstream pathways. Novel negative control mechanisms that act rapidly and are generated within the TCR signalosome have been recently uncovered. They are distinct from the regulatory mechanisms that are induced by 'classical' inhibitory receptors such as CD5, CTLA4 (cytotoxic T-lymphocyte antigen 4) and PD1 (programmed cell death 1). Rapid negative feedback mechanisms, such as those activated by the phosphatases SHP1 (SRC-homology-2-domain-containing protein tyrosine phosphatase 1) and the adaptor proteins DOK1 (downstream of kinase 1) and DOK2, might help to explain how T cells reject TCR signal noise that is generated by self ligands and allow ligand discrimination. Other negative feedback mechanisms, such as those activated by the serine/threonine kinase HPK1 (haematopoietic progenitor kinase 1) and the tyrosine phosphatase STS1 (suppressor of T-cell signalling 1), instead seem to modulate signal amplitude once the signal is initiated. When compromised, all the above mechanisms can cause spontaneous autoimmunity or increase the severity of experimentally-induced autoimmune disease. This Review focuses on recently described regulatory mechanisms that fine-tune T-cell receptor (TCR) signalling. Such mechanisms, which are rapid and intrinsic to the TCR signalosome, may explain how the TCR can discriminate true ligands from background noise and induce an appropriate T-cell response. The T-cell receptor (TCR) signalling machinery is central in determining the response of a T cell (establishing immunity or tolerance) following exposure to antigen. This process is made difficult by the narrow margin of self and non-self discrimination, and by the complexity of the genetic programmes that are induced for each outcome. Recent studies have identified novel negative feedback mechanisms that are rapidly induced by TCR engagement and that have key roles in the regulation of signal triggering and propagation. In vitro and in viv