T lymphocytes: Activation


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.


Acuto O and Michel F (2003) CD28‐mediated co‐stimulation: a quantitative support for TCR signalling. Nature Reviews Immunology 3: 939–951.

Costello PS, Gallagher M and Cantrell DA (2002) Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nature Immunology 3: 1082–1089.

Dodeller F and Schulze‐Koops H (2006) The p38 mitogen‐activated protein kinase signaling cascade in CD4 T cells. Arthritis Research and Therapy 8: 205.

Dustin ML and Depoil D (2011) New insights into the T cell synapse from single molecule techniques. Nature Reviews Immunology 11: 672–684.

Faure S, Salazar‐Fontana LI, Semichon M, et al. (2004) ERM proteins regulate cytoskeleton relaxation promoting T cell‐APC conjugation. Nature Immunology 5: 272–279.

Frauwirth KA, Riley JL, Harris MH, et al. (2002) The CD28 signaling pathway regulates glucose metabolism. Immunity 16: 769–777.

Genot E and Cantrell DA (2000) Ras regulation and function in lymphocytes. Current Opinion in Immunology 12: 289–294.

Hermiston ML, Xu Z and Weiss A (2003) CD45: a critical regulator of signaling thresholds in immune cells. Annual Review of Immunology 21: 107–137.

Isakov N and Altman A (2002) Protein kinase C(theta) in T cell activation. Annual Review of Immunology 20: 761–794.

Jacobs SR, Herman CE, Maciver NJ, et al. (2008) Glucose uptake is limiting in T cell activation and requires CD28‐mediated Akt‐dependent and independent pathways. Journal of Immunology 180: 4476–4486.

Jordan MS, Singer AL and Koretzky GA (2003) Adaptors as central mediators of signal transduction in immune cells. Nature Immunology 4: 110–116.

Kisseleva T, Bhattacharya S, Braunstein J and Schindler CW (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285: 1–24.

Menasche G, Kliche S, Chen EJ, et al. (2007) RIAM links the ADAP/SKAP‐55 signaling module to Rap1, facilitating T‐cell‐receptor‐mediated integrin activation. Molecular and Cellular Biology 27: 4070–4081.

van der Merwe PA and Dushek O (2011) Mechanisms for T cell receptor triggering. Nature Reviews Immunology 11: 47–55.

Mustelin T and Tasken K (2003) Positive and negative regulation of T‐cell activation through kinases and phosphatases. Biochemical Journal 371: 15–27.

Oh‐hora M and Rao A (2008) Calcium signaling in lymphocytes. Current Opinion in Immunology 20: 250–258.

Paster W, Bruger AM, Katsch K, et al. (2015) A THEMIS:SHP1 complex promotes T‐cell survival. EMBO Journal 34: 393–409.

Rincon M, Flavell RA and Davis RA (2000) The JNK and P38 MAP kinase signaling pathways in T cell‐mediated immune responses. Free Radical Biology & Medicine 28: 1328–1337.

Schamel WW and Alarcon B (2013) Organization of the resting TCR in nanoscale oligomers. Immunological Reviews 251: 13–20.

Smith‐Garvin JE, Koretzky GA and Jordan MS (2009) T cell activation. Annual Review of Immunology 27: 591–619.

Topalian SL, Drake CG and Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27: 450–461.

Wang S and Chen L (2004) Co‐signaling molecules of the B7‐CD28 family in positive and negative regulation of T lymphocyte responses. Microbes and Infection 6: 759–766.

Ward SG and Cantrell DA (2001) Phosphoinositide 3‐kinases in T lymphocyte activation. Current Opinion in Immunology 13: 332–338.

Wucherpfennig KW, Gagnon E, Call MJ, et al. (2010) Structural biology of the T‐cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harbor Perspectives in Biology 2: a005140.

Further Reading

Acuto O and Cantrell D (2000) T cell activation and the cytoskeleton. Annual Review of Immunology 18: 165–184.

Balagopalan L, Coussens NP, Sherman E, et al. (2010) The LAT story: a tale of cooperativity, coordination, and choreography. Cold Spring Harbor Perspectives in Biology 2: a005512.

Blanco R and Alarcon B (2012) TCR Nanoclusters as the Framework for Transmission of Conformational Changes and Cooperativity. Frontiers in Immunology 3: 115.

Borroto A, Arellano I, Dopfer EP, et al. (2013) Nck recruitment to the TCR required for ZAP70 activation during thymic development. Journal of Immunology 190: 1103–1112.

Bridgeman JS, Sewell AK, Miles JJ, et al. (2012) Structural and biophysical determinants of alphabeta T‐cell antigen recognition. Immunology 135: 9–18.

Chakraborty AK and Weiss A (2014) Insights into the initiation of TCR signaling. Nature Immunology 15: 798–807.

Dustin ML, Chakraborty AK and Shaw AS (2010) Understanding the structure and function of the immunological synapse. Cold Spring Harbor Perspectives in Biology 2: a002311.

Ferez M, Castro M, Alarcon B and van Santen HM (2014) Cognate peptide‐MHC complexes are expressed as tightly apposed nanoclusters in virus‐infected cells to allow TCR crosslinking. Journal of Immunology 192: 52–58.

Yokosuka T, Sakata‐Sogawa K, Kobayashi W, et al. (2005) Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP‐76. Nature Immunology 6: 1253–1262.

Zehn D, King C, Bevan MJ and Palmer E (2012) TCR signaling requirements for activating T cells and for generating memory. Cellular and Molecular Life Sciences 69: 1565–1575.

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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]