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16-02-2017 | Image

Figure 4: The immune-checkpoint axis that serves to maintain self-tolerance and prevent autoimmunity.

a | Components of the immune synapse. T cells recognize antigens presented on the MHC by the TCR. The fate of T cells upon antigen recognition is determined by the additional ligand–receptor interactions between the T cells and APCs (or tumour cells). The co-stimulatory signals activated via CD28, 4-1BB (CD137), OX40, and CD27 promote activation of T cells, whereas those sent via CTLA-4 and PD-1 decrease T-cell activation. Various treatment modalities are being developed to modulate these signals. Antagonistic antibodies have been developed that target co-stimulatory signals delivered via OX40–OX40L, 4-1BB (CD137)–4-1BBL (CD137L), and CD27–CD70 interaction. Both agonistic and antagonistic antibodies that target the CD40–CD40L interaction are in development. Immune-checkpoint inhibitors target the inhibitory signals transduced through the PD-1–PD-L1 axis and CTLA-4 interactions. Molecules engaged in co-stimulatory signalling are coloured in pink, and those involved in inhibitory signalling are coloured in red. b | Mechanism of T-cell activation at the tumour site and the lymph node. APCs take up TAAs at the site of tumour. The APCs migrate to the lymph node, where they present the TAA to naive (inactive) T cells. The specific T cells that recognize the TAA are activated (primed) via TCR-mediated signalling as well as co-stimulation through CD28 and CD80 and/or CD86 interactions. T-cell activation is interrupted when CTLA-4 is mobilized to the cell surface from intracellular stores and competes with CD28 for interaction with CD80 and CD86. The activated (primed) T cells circulate to the peripheral tissues and organs, and will be reactivated upon re-challenge with the TAA at the tumour site. Activation of T cells in the periphery is decreased upon expression of PD-1 on the surface of activated T cells after its transcriptional activation and engagement with its ligand PD-L1/PD-L2 that can be expressed on the tumour cells or on other immune cells in the tumour microenvironment. Abbreviations: APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1; PD-L2, programmed cell death 1 ligand 2; TAA, tumour-associated antigen; TCR, T-cell receptor.

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