T lymphocytes: Activation

Abstract

T‐lymphocyte activation is triggered by interaction of the T‐cell receptor (TCR) with antigens. Full activation of these immune cells requires three distinct signals: TCR activation, costimulatory receptor engagement (i.e. CD28) and cytokine recognition through their receptors (i.e. IL‐2). The immunological synapse forms at the contact between T lymphocytes and antigen‐presenting cells (APC), providing a platform where receptors form microclusters, thus enhancing cooperative signalling through conformational changes. Initial steps of TCR signalling are transmitted through these conformational changes to induce a recruitment cascade of adaptor proteins, tyrosine kinases, coreceptors or integrins. The distinct signalling pathways activated upon antigen binding to the TCR include Ras/MAPK, PI3K, Rho/Rac or Ca2+/calcineurin, among others, as well as negative regulators. All these integrated signals result in T‐lymphocyte progression towards unique proliferative and differentiation patterns that modulate immune responses.

Key Concepts

  • T‐lymphocyte activation is triggered by antigen recognition by TCRs on T cells, giving rise to the immunological synapse.
  • Costimulatory receptors and cytokines are also required for full activation of T cells.
  • Conformational changes in clustered TCR at the immunological synapse transmit signals towards coreceptors, tyrosine kinases or adaptors.
  • Downstream effectors of the TCR include proteins from many signalling pathways, that is Ras/MAPK, PI3K, Rho/Rac or PKCθ, which ultimately modulate transcription factors such as AP‐1, NF‐κB or NFAT.
  • Activation of diverse signalling cascades through the TCR results in clonal expansion and differentiation of T lymphocytes.
  • TCR clustering allows for signal regulation by maintaining a spatiotemporal distinction at the immunological synapse between active TCRs and TCRs to be recycled or degraded.

Keywords: TCR; immunological synapse; immunological signalling pathways; TCR clustering; costimulatory receptors; cytokine receptors

Figure 1. T cells need three signals in order for full activation to be achieved. Signal 1 takes place upon T‐cell receptor (TCR) engagement with antigens bound to major histocompatibility complex (MHC) on antigen‐presenting cells (APC). Signal 2 comes from costimulatory receptors such as CD28 when it encounters its cognate receptor ligands on APC, namely CD80 and CD86. Signal 3 is provided by varied cytokine receptors, which modulate the other two signals to induce specific T‐cell differentiation.
Figure 2. Schematic depicting the diverse signalling cascades triggered by TCR and its costimulatory receptor CD28. Arrows represent recruitment or enzymatic modifications, such as phosphorylation of downstream effectors (shown as an encircled ‘P’).
Figure 3. TCR clusters are engaged sequentially at the immunological synapse. Previously formed TCR nanoclusters are detected by peptides on major histocompatibility complex (pMHC) clusters at the T‐lymphocyte/APC contact site, which triggers TCR‐mediated cytoskeletal reorganisation to allow for larger TCR clusters to form (microclusters) and sustain the TCR signal. Microclusters then travel towards the centre of the immunological synapse, forming the central supramolecular activation cluster (cSMAC), where signalling through the TCR is scarce and TCRs are internalised for degradation or recycling.
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Oeste, Clara L, and Alarcón, Balbino(Jun 2016) T lymphocytes: Activation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001184.pub2]