T Cell Co-inhibitory Receptors: Functions and Signalling Mechanisms

T cell activation is a central event in the adaptive immune response and essentially begins with the recognition of an antigenic peptide in the context of a major histocompatibility complex (MHC) on an antigen-presenting cell by the T cell receptor (TCR). The process of T cell activation consists of an orchestration of various functional modules such as actin polymerization, cell surface receptor patterning, calcium fluxing, immunological synapse formation, enhanced adhesion and gene transcription. These modules are mediated by a number of signalling proteins through inducible phosphorylation, enzyme activation and protein-protein & protein-lipid interactions. This complex and dynamic interplay of signalling events governs the decisions the T cell makes in terms of gene expression, proliferation, differentiation, survival and migration. These outcomes are influenced by the magnitude, duration and context of the activation signals. The activation signals have the potential to be modulated by a family of receptors termed, co-inhibitory receptors that include PD-1, LAG-3, TIM-3 and CTLA-4. Co-inhibitory receptors modulate signalling by utilising mechanisms such as ectodomain competition with counter receptors and by the use of intracellular mediators such as protein phosphatases. Co-inhibitory receptors can act as threshold-setters, modulators, check-points and feedback mechanisms that can potentially fine tune the quality and magnitude of the T cell immune response. Given the key roles of these receptors in modulating the immune response, they are increasingly being targeted for immune intervention in a variety of disease settings. This review discusses current understanding of the role of co-inhibitory receptors in influencing T cell signalling. T Cell Co-inhibitory Receptors: Functions and Signalling Mechanisms