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Definition

Immune checkpoint molecules are key modulators of the anti-tumour T cell immune response. They are present on T cells, antigen-presenting cells (APCs) and tumour cells; their interaction activates either inhibitory or activating immune signalling pathways. Examples of inhibitory immune checkpoints shown to induce a negative signal to T cells are:

  • Cytotoxic T-lymphocyte antigen 4 (CTLA-4, also known as CD152)
  • Programmed cell death protein 1 (PD-1, also known as CD279)
  • Lymphocyte-activation gene 3 (LAG-3)
  • T cell immunoglobulin and mucin domain 3 (TIM-3)
  • V-domain immunoglobulin suppressor of T cell activation (VISTA)

Inhibitory immune checkpoints play a vital role in maintaining immune self-tolerance. Indeed, negative co-stimulatory signals help to prevent T cells from showing autoimmune reactions.On the other hand, co-stimulatory immune checkpoints have been shown to enhance T cell expansion and survival. Examples are:

  • D40
  • OX40 (also known as CD134)
  • 4-1BB (also known as CD137)
  • Glucocorticoid-induced tumour necrosis factor (TNF) receptor (GITR)
  • Inducible T cell co-stimulator (ICOS, also known as CD278)

Other intracellular metabolic pathways play a critical role in the activation of immune cells and could, by extension, be considered as immune checkpoints. For instance, in tumour cells and myeloid cells, indoleamine 2, 3-dioxygenase (IDO) and arginase are key enzymes which, by depleting amino acids, can inhibit the effector functions of T cells. However, we will focus here on immune checkpoint molecules: membrane-expressed receptors and ligands, which determine, at the level of the intercellular synapse, if an immune cell becomes activated or inhibited. We will also concentrate on immune checkpoints involved in the activation of T cells, as they are of current clinical interest. However, other immune checkpoints play a critical role for the modulation of other subsets of immune cells (e.g. CD40 for B cells).

Preface Immune Synapse

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