Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

T cell receptor signalling networks: branched, diversified and bounded

Nature Reviews Immunology volume 13, pages 257–269 (2013)Cite this article

Subjects

Key Points

  • T cell signalling controls the outcome of T cell receptor (TCR) engagement. That outcome can be either beneficial, for example, by the initiation of responses leading to the elimination of pathogens, or detrimental, by leading to excessive inflammation and autoimmunity.

  • TCR triggering initiates signalling cascades that are intricately branched rather than simply top-down cascades that progress in a linear manner. Multiple signalling cascades are triggered following TCR engagement, resulting in processes such as integrin activation, cytoskeletal rearrangement, metabolic changes and the production of transcription factors, enabling the T cell to proliferate and to differentiate.

  • Feedback pathways that terminate T cell signalling are as important for a balanced immune response as feedforward pathways that initiate signalling. Disruption of feedforward pathways compromises the ability to mount effective responses, and disruption of feedback pathways predisposes to inflammation and potential autoimmune sequela.

  • Linker for activation of T cells (LAT) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) have roles in activating TCR feedback loops, as revealed from studies of individuals with point mutations or of mice with loss of expression of these molecules. Disruption of the normal function of these molecules can lead to inflammatory and autoimmune disorders.

  • Spatiotemporal regulation of the interactions among signalling molecules is critical for balanced T cell activation. These processes are becoming better understood through advances in technologies that permit single-molecule resolution of signalling interactions.

  • Mutations in key signalling molecules are becoming increasingly associated with autoimmune conditions. Understanding their complete roles in TCR signalling is essential if they are to be used as novel targets for therapeutic interventions.

Abstract

Engagement of antigen-specific T cell receptors (TCRs) is a prerequisite for T cell activation. Acquisition of appropriate effector T cell function requires the participation of multiple signals from the T cell microenvironment. Trying to understand how these signals integrate to achieve specific functional outcomes while maintaining tolerance to self is a major challenge in lymphocyte biology. Several recent publications have provided important insights into how dysregulation of T cell signalling and the development of autoreactivity can result if the branching and integration of signalling pathways are perturbed. We discuss how these findings highlight the importance of spatial segregation of individual signalling components as a way of regulating T cell responsiveness and immune tolerance.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of TCR signalling.
Figure 2: Negative feedback.
Figure 3: Key concepts in spatiotemporal control of LAT.
Figure 4: Mechanisms of TCR mediated inside-out signalling to integrins.

Similar content being viewed by others

References

  1. Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J. & Davis, M. M. Virus-specific CD4+ memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–383 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Tanchot, C., Lemonnier, F. A., Perarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Seddon, B. & Zamoyska, R. Regulation of peripheral T-cell homeostasis by receptor signalling. Curr. Opin. Immunol. 15, 321–324 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Palacios, E. H. & Weiss, A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 23, 7990–8000 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Parsons, S. J. & Parsons, J. T. Src family kinases, key regulators of signal transduction. Oncogene 23, 7906–7909 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Salmond, R. J., Filby, A., Qureshi, I., Caserta, S. & Zamoyska, R. T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol. Rev. 228, 9–22 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Seddon, B. & Zamoyska, R. TCR signals mediated by Src family kinases are essential for the survival of naive T cells. J. Immunol. 169, 2997–3005 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Stefanova, I., Dorfman, J. R. & Germain, R. N. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420, 429–434 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Acuto, O., Di Bartolo, V. & Michel, F. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nature Rev. Immunol. 8, 699–712 (2008). A comprehensive review detailing negative feedback mechanisms in proximal TCR signalling, including extensive definitions of signalling modules to help consider signalling in terms of interacting groups rather than as purely linear processes.

    Article  CAS  Google Scholar 

  11. Veillette, A., Bookman, M. A., Horak, E. M. & Bolen, J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 55, 301–308 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. Artyomov, M. N., Lis, M., Devadas, S., Davis, M. M. & Chakraborty, A. K. CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery. Proc. Natl Acad. Sci. USA 107, 16916–16921 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ɛ cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Kim, S. T. et al. TCR mechanobiology: torques and tunable structures linked to early T cell signaling. Front. Immunol. 3, 76 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Davis, S. J. & van der Merwe, P. A. The kinetic-segregation model: TCR triggering and beyond. Nature Immunol. 7, 803–809 (2006).

    Article  CAS  Google Scholar 

  16. James, J. R. & Vale, R. D. Biophysical mechanism of T-cell receptor triggering in a reconstituted system. Nature 487, 64–69 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Lovatt, M. et al. Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response. Mol. Cell. Biol. 26, 8655–8665 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Deindl, S. et al. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 129, 735–746 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Boggon, T. J. & Eck, M. J. Structure and regulation of Src family kinases. Oncogene 23, 7918–7927 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Yamaguchi, H. & Hendrickson, W. A. Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation. Nature 384, 484–489 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Rhee, I. & Veillette, A. Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nature Immunol. 13, 439–447 (2012).

    Article  CAS  Google Scholar 

  22. Schmedt, C. et al. Csk controls antigen receptor-mediated development and selection of T-lineage cells. Nature 394, 901–904 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Schmedt, C. & Tarakhovsky, A. Autonomous maturation of α/β T lineage cells in the absence of COOH-terminal Src kinase (Csk). J. Exp. Med. 193, 815–826 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Hermiston, M. L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. McNeill, L. et al. The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity 27, 425–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Zikherman, J. et al. CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development. Immunity 32, 342–354 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Cloutier, J. F., Chow, L. M. & Veillette, A. Requirement of the SH3 and SH2 domains for the inhibitory function of tyrosine protein kinase p50csk in T lymphocytes. Mol. Cell. Biol. 15, 5937–5944 (1995).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Nika, K. et al. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32, 766–777 (2010). This paper shows that a large proportion of LCK is constitutively active in resting T cells and that TCR triggering does not alter the proportion of phosphorylated LCK, leading to the conclusion that TCR triggering is likely to be controlled by changes in the local concentration of active LCK rather than by switching LCK between inactive and active states.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Rossy, J., Owen, D. M., Williamson, D. J., Yang, Z. & Gaus, K. Conformational states of the kinase Lck regulate clustering in early T cell signaling. Nature Immunol. 14, 82–89 (2013). Supported by evidence from high-resolution microscopy and the reconstitution of Jurkat T cells with various LCK mutants, this study proposes that LCK clustering upon TCR triggering is determined by the conformation of LCK.

    Article  CAS  Google Scholar 

  30. Horejsi, V., Zhang, W. & Schraven, B. Transmembrane adaptor proteins: organizers of immunoreceptor signalling. Nature Rev. Immunol. 4, 603–616 (2004).

    Article  CAS  Google Scholar 

  31. Borger, J., Filby, A. & Zamoyska, R. Differential polarisation of C-terminal Src kinase between naïve and antigen-experienced CD8+ T cells. J. Immunol. 20 Feb 2013 (doi:10.4049/jimmunol.1202408)

    Article  CAS  PubMed  Google Scholar 

  32. Schoenborn, J. R., Tan, Y. X., Zhang, C., Shokat, K. M. & Weiss, A. Feedback circuits monitor and adjust basal Lck-dependent events in T cell receptor signaling. Sci. Signal. 4, ra59 (2011). This study shows that CSK and CD45 regulate the activity of LCK and influence feedback circuits that affect the threshold of activation in T cells.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kawabuchi, M. et al. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999–1003 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Davidson, D., Bakinowski, M., Thomas, M. L., Horejsi, V. & Veillette, A. Phosphorylation-dependent regulation of T-cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Mol. Cell. Biol. 23, 2017–2028 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Dobenecker, M. W., Schmedt, C., Okada, M. & Tarakhovsky, A. The ubiquitously expressed Csk adaptor protein Cbp is dispensable for embryogenesis and T-cell development and function. Mol. Cell. Biol. 25, 10533–10542 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Xu, S., Huo, J., Tan, J. E. & Lam, K. P. Cbp deficiency alters Csk localization in lipid rafts but does not affect T-cell development. Mol. Cell. Biol. 25, 8486–8495 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Smida, M., Posevitz-Fejfar, A., Horejsi, V., Schraven, B. & Lindquist, J. A. A novel negative regulatory function of the phosphoprotein associated with glycosphingolipid-enriched microdomains: blocking Ras activation. Blood 110, 596–615 (2007). The authors show that PAG interacts with negative regulators of T cell signalling, including CSK, in primary human T cells and that knocking down PAG with siRNA enhances SFK activity and RAS activation.

    Article  CAS  PubMed  Google Scholar 

  38. Dong, S. et al. T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J. Exp. Med. 203, 2509–2518 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Yasuda, T. et al. Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. Int. Immunol. 19, 487–495 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, S. Q. et al. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell 13, 341–355 (2004).

    Article  PubMed  Google Scholar 

  41. Bivona, T. G. et al. Phospholipase Cγ activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343–350 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Inder, K. et al. Activation of the MAPK module from different spatial locations generates distinct system outputs. Mol. Biol. Cell 19, 4776–4784 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Lockyer, P. J., Kupzig, S. & Cullen, P. J. CAPRI regulates Ca2+-dependent inactivation of the Ras-MAPK pathway. Curr. Biol. 11, 981–986 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Perez de Castro, I., Bivona, T. G., Philips, M. R. & Pellicer, A. Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus. Mol. Cell. Biol. 24, 3485–3496 (2004).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Daniels, M. A. et al. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444, 724–729 (2006). The first study to report that different strengths of TCR signalling in thymocytes alters the compartmentalization of RAS and MAPK to different subcellular locations and therefore propagates signals to different branches of the signalling cascade.

    Article  CAS  PubMed  Google Scholar 

  47. Balagopalan, L., Coussens, N. P., Sherman, E., Samelson, L. E. & Sommers, C. L. The LAT story: a tale of cooperativity, coordination, and choreography. Cold Spring Harb Perspect Biol 2, a005512 (2010).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Finco, T. S., Kadlecek, T., Zhang, W., Samelson, L. E. & Weiss, A. LAT is required for TCR-mediated activation of PLCγ1 and the Ras pathway. Immunity 9, 617–626 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, W. et al. Essential role of LAT in T cell development. Immunity 10, 323–332 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Mingueneau, M. et al. Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 31, 197–208 (2009). This paper describes the surprising finding that loss of LAT in peripheral T cells does not inhibit but rather dysregulates TCR signalling, resulting in unrestrained T cell proliferation and the development of pathology, highlighting a previously unknown role for LAT in regulating TCR signals (for further details see reference 53).

    Article  CAS  PubMed  Google Scholar 

  51. Roncagalli, R. et al. Lymphoproliferative disorders involving T helper effector cells with defective LAT signalosomes. Semin. Immunopathol. 32, 117–125 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Chevrier, S., Genton, C., Malissen, B., Malissen, M. & Acha-Orbea, H. Dominant role of CD80-CD86 over CD40 and ICOSL in the massive polyclonal B Cell activation mediated by LATY136F CD4+ T cells. Front. Immunol. 3, 27 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  53. Roncagalli, R., Mingueneau, M., Gregoire, C., Malissen, M. & Malissen, B. LAT signaling pathology: an “autoimmune” condition without T cell self-reactivity. Trends Immunol. 31, 253–259 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Rouquette-Jazdanian, A. K., Sommers, C. L., Kortum, R. L., Morrison, D. K. & Samelson, L. E. LAT-independent Erk activation via Bam32-PLC-γ1-Pak1 complexes: GTPase-independent Pak1 activation. Mol. Cell 48, 298–312 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Koretzky, G. A., Abtahian, F. & Silverman, M. A. SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nature Rev. Immunol. 6, 67–78 (2006).

    Article  CAS  Google Scholar 

  56. Chen, H. & Kahn, M. L. Reciprocal signaling by integrin and nonintegrin receptors during collagen activation of platelets. Mol. Cell. Biol. 23, 4764–4777 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).

    CAS  PubMed  Google Scholar 

  58. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Yokosuka, T. et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nature Immunol. 6, 1253–1262 (2005).

    Article  CAS  Google Scholar 

  60. Bunnell, S. C. et al. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J. Cell Biol. 158, 1263–1275 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Seminario, M. C. & Bunnell, S. C. Signal initiation in T-cell receptor microclusters. Immunol. Rev. 221, 90–106 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Dustin, M. L. & Depoil, D. New insights into the T cell synapse from single molecule techniques. Nature Rev. Immunol. 11, 672–684 (2011). A comprehensive and timely review describing new super-resolution techniques to visualize TCR signalling at a nano- or single-molecular level and how this technology has influenced our understanding of TCR triggering.

    Article  CAS  Google Scholar 

  63. Lillemeier, B. F. et al. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nature Immunol. 11, 90–96 (2010).

    Article  CAS  Google Scholar 

  64. Sherman, E. et al. Functional nanoscale organization of signaling molecules downstream of the T cell antigen receptor. Immunity 35, 705–720 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Purbhoo, M. A. et al. Dynamics of subsynaptic vesicles and surface microclusters at the immunological synapse. Sci. Signal. 3, ra36 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Williamson, D. J. et al. Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events. Nature Immunol. 12, 655–662 (2011). References 63–66 present evidence for various models of how and where LAT molecules may localize and interact with the TCR.

    Article  CAS  Google Scholar 

  67. Barda-Saad, M. et al. Cooperative interactions at the SLP-76 complex are critical for actin polymerization. EMBO J. 29, 2315–2328 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Bubeck Wardenburg, J. et al. Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9, 607–616 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Singleton, K. L. et al. Spatiotemporal patterning during T cell activation is highly diverse. Sci. Signal. 2, ra15 (2009). This paper follows the spatiotemporal patterning of 32 individual signalling components in primary mouse T cells stimulated by professional APCs and a variety of ligands of differing affinity. This systems level approach shows that patterning is highly diverse.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Singleton, K. L. et al. Itk controls the spatiotemporal organization of T cell activation. Sci. Signal. 4, ra66 (2011).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Valitutti, S., Dessing, M., Aktories, K., Gallati, H. & Lanzavecchia, A. Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton. J. Exp. Med. 181, 577–584 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Delon, J., Bercovici, N., Liblau, R. & Trautmann, A. Imaging antigen recognition by naive CD4+ T cells: compulsory cytoskeletal alterations for the triggering of an intracellular calcium response. Eur. J. Immunol. 28, 716–729 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Dustin, M. L. & Cooper, J. A. The immunological synapse and the actin cytoskeleton: molecular hardware for T cell signaling. Nature Immunol. 1, 23–29 (2000).

    Article  CAS  Google Scholar 

  74. Berg, L. J., Finkelstein, L. D., Lucas, J. A. & Schwartzberg, P. L. Tec family kinases in T lymphocyte development and function. Annu. Rev. Immunol. 23, 549–600 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Burbach, B. J., Medeiros, R. B., Mueller, K. L. & Shimizu, Y. T-cell receptor signaling to integrins. Immunol. Rev. 218, 65–81 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Dustin, M. L. T-cell activation through immunological synapses and kinapses. Immunol. Rev. 221, 77–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Sixt, M., Bauer, M., Lammermann, T. & Fassler, R. β1 integrins: zip codes and signaling relay for blood cells. Curr. Opin. Cell Biol. 18, 482–490 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Nguyen, K., Sylvain, N. R. & Bunnell, S. C. T cell costimulation via the integrin VLA-4 inhibits the actin-dependent centralization of signaling microclusters containing the adaptor SLP-76. Immunity 28, 810–821 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Adachi, K. & Davis, M. M. T-cell receptor ligation induces distinct signaling pathways in naive versus antigen-experienced T cells. Proc. Natl Acad. Sci. USA 108, 1549–1554 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gloerich, M. & Bos, J. L. Regulating Rap small G-proteins in time and space. Trends Cell Biol. 21, 615–623 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Bivona, T. G. et al. Rap1 up-regulation and activation on plasma membrane regulates T cell adhesion. J. Cell Biol. 164, 461–470 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Sebzda, E., Bracke, M., Tugal, T., Hogg, N. & Cantrell, D. A. Rap1A positively regulates T cells via integrin activation rather than inhibiting lymphocyte signaling. Nature Immunol. 3, 251–258 (2002).

    Article  CAS  Google Scholar 

  83. Epler, J. A., Liu, R., Chung, H., Ottoson, N. C. & Shimizu, Y. Regulation of β1 integrin-mediated adhesion by T cell receptor signaling involves ZAP-70 but differs from signaling events that regulate transcriptional activity. J. Immunol. 165, 4941–4949 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Hogg, N., Patzak, I. & Willenbrock, F. The insider's guide to leukocyte integrin signalling and function. Nature Rev. Immunol. 11, 416–426 (2011). A comprehensive review focusing on LFA1 activation in T cells, discussing both inside-out and outside-in integrin signalling.

    Article  CAS  Google Scholar 

  85. Raab, M. et al. T cell receptor “inside-out” pathway via signaling module SKAP1-RapL regulates T cell motility and interactions in lymph nodes. Immunity 32, 541–556 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Au-Yeung, B. B. et al. A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity. Nature Immunol. 11, 1085–1092 (2010). A study highlighting the adaptor properties of ZAP70 that are important for inside-out activation of LFA1, a pathway crucial for T Reg cell function.

    Article  CAS  Google Scholar 

  87. Marski, M., Kandula, S., Turner, J. R. & Abraham, C. CD18 is required for optimal development and function of CD4+CD25+ T regulatory cells. J. Immunol. 175, 7889–7897 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Li, L. et al. Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo. J. Immunol. 175, 3133–3139 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Mempel, T. R., Henrickson, S. E. & Von Andrian, U. H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Cemerski, S. et al. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 26, 345–355 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Huppa, J. B., Gleimer, M., Sumen, C. & Davis, M. M. Continuous T cell receptor signaling required for synapse maintenance and full effector potential. Nature Immunol. 4, 749–755 (2003).

    Article  CAS  Google Scholar 

  92. Cloutier, J. F. & Veillette, A. Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 15, 4909–4918 (1996).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  93. Cloutier, J. F. & Veillette, A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med. 189, 111–121 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Brownlie, R. J. et al. Lack of the phosphatase PTPN22 increases adhesion of murine regulatory T cells to improve their immunosuppressive function. Sci. Signal. 5, ra87 (2012). Mice that lack PTPN22 were shown to have increased numbers of T Reg cells with enhanced function, which were capable of restraining hyperactive Ptpn22−/− T effector cells and maintaining T cell tolerance. The increased T Reg cell functionality could be explained at least in part by increased LFA1 adhesion (see also reference 86).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Hasegawa, K. et al. PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303, 685–689 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Bottini, N., Vang, T., Cucca, F. & Mustelin, T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin. Immunol. 18, 207–213 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Zhang, J. et al. The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness. Nature Genet. 43, 902–907 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. Vang, T. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nature Genet. 37, 1317–1319 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931–935 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Mann, M. Functional and quantitative proteomics using SILAC. Nature Rev. Mol. Cell Biol. 7, 952–958 (2006).

    Article  CAS  Google Scholar 

  103. Bendall, S. C., Nolan, G. P., Roederer, M. & Chattopadhyay, P. K. A deep profiler's guide to cytometry. Trends Immunol. 33, 323–332 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Basiji, D. A., Ortyn, W. E., Liang, L., Venkatachalam, V. & Morrissey, P. Cellular image analysis and imaging by flow cytometry. Clin. Lab. Med. 27, 653–670, (2007).

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank their many colleagues who have contributed helpful discussions, particularly R. Salmond and P. Travers for critical comments on the manuscript. Special thanks to P. Travers for help with the figures and for suggesting the title. The authors also thank the Wellcome Trust, UK, for funding.

Author information

Authors and Affiliations

  1. Institute for Immunology and Infection Research, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JT, UK

    Rebecca J. Brownlie & Rose Zamoyska

Authors
  1. Rebecca J. Brownlie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rose Zamoyska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rose Zamoyska.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Rose Zamoyska's homepage

Glossary

Immunological synapse

The immunological synapse forms at the interface between the T cell receptor (TCR) and antigen-presenting cell and is traditionally characterized by a 'bull's eye' structure consisting of a central supramolecular activation cluster (cSMAC), a peripheral SMAC and a distal SMAC, creating the site at which TCR signal transduction is coordinated.

Tonic signals

Induced by low-affinity engagement of the T cell receptor (TCR) by self-peptide–MHC complexes. Tonic signals are important for the maintenance and the homeostatic proliferation of T cells.

LAT-signalling pathology

An autoimmune lymphoproliferative disorder that results in excessive amounts of TH2 cytokines and polyclonal B cell activation with hypergammaglobulinaemia (IgG1 and IgE), which is caused by mutations in key linker for activation of T cells (LAT) tyrosine residues or in the absence of LAT.

Cental supramolecular activation cluster

(cSMAC). After T cell receptor (TCR) engagement, the TCRs accumulate into a cluster at the interface between the T cell and antigen-presenting cell, termed the cSMAC. The cSMAC is surrounded by a ring of LFA1 that constitutes the peripheral SMAC. The most external ring is called the distal SMAC that is rich in large proteins, such as CD45, and in actin.

TCR microclusters

TCR microclusters are generated at the initial contact region of the T cell receptor (TCR)–antigen-presenting cell (APC) interface in the first minute of TCR engagement, before formation of the full immunological synapse. They consist of approximately 30–300 TCRs together with signalling molecules, and function as a minimal signalling unit, which translocates to the centre of the TCR–APC interface to form the central supramolecular activation cluster of the immunological synapse.

Inside-out signals

Integrins generate signal transduction in two directions, moving from the extracellular microenvironment into the cell cytoplasm (outside-in signalling) and from the cytoplasm out to the extracellular domain of the receptor (inside-out signalling).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brownlie, R., Zamoyska, R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol 13, 257–269 (2013). https://doi.org/10.1038/nri3403

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3403

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing