Figure 1 The role of CTLA4 and PD1 in T cell activation

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Figure 1 The role of CTLA4 and PD1 in T cell activation Figure 1 | The role of CTLA4 and PD1 in T cell activation. a | The current paradigm for T cell activation, including T cell receptor (TCR) ligation and CD80/CD86 and CD28 co-stimulation, is shown. b | Cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are upregulated after T cell activation, serving as a natural checkpoint to T cell activation. CTLA4 then binds to CD80 and/or CD86 (owing to a higher affinity interaction), discouraging engagement with CD28. Regulatory T (Treg) cells also express CTLA4, which also sequesters CD80 and/or CD86 and might promote cleavage of CD80/CD86 from the antigen-presenting cell (APC) surface through reciprocal signalling or transcytosis. The immunosuppressive effects of Treg cells can also be CTLA4-mediated via reciprocal signalling to APCs to downregulate CD80 and/or CD86 expression, transcytosis of molecules and production of relevant cytokines (forkhead box protein 3 (FOXP3)-dependent). PD1 ligation with programmed cell death 1 ligand 1 (PDL1) provides a direct inhibitory signal to T cells. c | The effects of checkpoint inhibition are shown. Antibody blockade of CTLA4 restores co-stimulation between CD28 and CD80 and/or CD86, and blockade of PD1 alleviates this inhibitory pathway. As CTLA4 is essential for Treg cell function, inhibition of this pathway affects their suppressive capabilities. On the basis of evidence from animal models, we hypothesize that the immune enterocolitis seen with checkpoint inhibition is secondary to hyper-activated effector T (Teff) cells targeting luminal antigens (that is, those from the microbiota and dietary products) and to loss of functional Treg cells. Ag, antigen; MHC, major histocompatibility complex; TGFβ, transforming growth factor-β. Samaan, M. A. et al. (2018) Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2018.14