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Regulatory mechanisms in T cell receptor signalling

Abstract

The remarkable T cell receptor (TCR) performs essential functions in the initiation of intracellular signals required for T cell development, repertoire selection and effector responses to foreign antigens. How TCR signals elicit such diverse cellular responses and outcomes remains a major question for investigation. Recent years have witnessed important advances in our understanding of the regulatory processes that control and modulate the TCR signalling response. Here, we review newly identified mechanisms for the regulation of TCR signalling and then discuss how the TCR signalling response is regulated to control two critical cellular processes — namely, positive selection and T cell homeostasis.

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Fig. 1: Overview of the major TCR signalling pathways.
Fig. 2: Regulation of LCK and ZAP70 activation.
Fig. 3: Modulation of TCR signalling potential by developmental regulation of signalling effectors and regulators.
Fig. 4: Dynamic tuning of TCR signalling to self-peptide–MHC complexes by CD5.

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References

  1. Samelson, L. E. & Klausner, R. D. The T cell antigen receptor. Structure and mechanism of activation. Ann. NY Acad. Sci. 540, 1–3 (1988).

    Article  PubMed  CAS  Google Scholar 

  2. Birnbaum, M. E. et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157, 1073–1087 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hochweller, K. et al. Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc. Natl Acad. Sci. USA 107, 5931–5936 (2010).

    Article  PubMed  Google Scholar 

  4. Chakraborty, A. K. & Weiss, A. Insights into the initiation of TCR signaling. Nat. Immunol. 15, 798–807 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Wang, J. H. & Reinherz, E. L. The structural basis of alphabeta T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol. Rev. 250, 102–119 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Huppa, J. B. & Davis, M. M. T cell-antigen recognition and the immunological synapse. Nat. Rev. Immunol. 3, 973–983 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. Love, P. E. & Hayes, S. M. ITAM-mediated signaling by the T cell antigen receptor. Cold Spring Harb. Perspect. Biol. 2, a002485 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Cantrell, D. T cell antigen receptor signal transduction pathways. Annu. Rev. Immunol. 14, 259–274 (1996).

    Article  PubMed  CAS  Google Scholar 

  9. Nika, K. et al. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32, 766–777 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Ballek, O., Valecka, J., Manning, J. & Filipp, D. The pool of preactivated Lck in the initiation of T cell signaling: a critical re-evaluation of the Lck standby model. Immunol. Cell Biol. 93, 384–395 (2015).

    Article  PubMed  CAS  Google Scholar 

  11. Philipsen, L. et al. De novo phosphorylation and conformational opening of the tyrosine kinase Lck act in concert to initiate T cell receptor signaling. Sci. Signal. 10, eaaf4736 (2017). This study provides evidence that the initiation of TCR signalling requires de novo phosphorylation of LCK.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Balagopalan, L., Kortum, R. L., Coussens, N. P., Barr, V. A. & Samelson, L. E. The linker for activation of T cells (LAT) signaling hub: from signaling complexes to microclusters. J. Biol. Chem. 290, 26422–26429 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Stirnweiss, A. et al. T cell activation results in conformational changes in the Src family kinase Lck to induce its activation. Sci. Signal. 6, ra13 (2013).

    Article  PubMed  CAS  Google Scholar 

  15. Pao, L. I., Badour, K., Siminovitch, K. A. & Neel, B. G. Nonreceptor protein-tyrosine phosphatases in immune cell signaling. Annu. Rev. Immunol. 25, 473–523 (2007).

    Article  PubMed  CAS  Google Scholar 

  16. Li, J. P. et al. The phosphatase JKAP/DUSP22 inhibits T cell receptor signalling and autoimmunity by inactivating Lck. Nat. Commun. 5, 3618 (2014).

    Article  PubMed  CAS  Google Scholar 

  17. Douglass, A. D. & Vale, R. D. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Cell 121, 937–950 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Bunnell, S. C. et al. Persistence of cooperatively stabilized signaling clusters drives T cell activation. Mol. Cell. Biol. 26, 7155–7166 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. 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. Nat. Immunol. 14, 82–89 (2013). This paper shows the link between the phosphorylation status and conformational state of LCK and its ability to form microclusters in T cells.

    Article  PubMed  CAS  Google Scholar 

  20. Joung, I. et al. Modification of Ser59 in the unique N-terminal region of tyrosine kinase p56lck regulates specificity of its Src homology 2 domain. Proc. Natl Acad. Sci. USA 92, 5778–5782 (1995).

    Article  PubMed  CAS  Google Scholar 

  21. Stefanova, I. et al. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4, 248–254 (2003).

    Article  PubMed  CAS  Google Scholar 

  22. Chiang, G. G. & Sefton, B. M. Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 276, 23173–23178 (2001).

    Article  PubMed  CAS  Google Scholar 

  23. Paster, W. et al. A THEMIS:SHP1 complex promotes T cell survival. EMBO J. 34, 393–409 (2015).

    Article  PubMed  CAS  Google Scholar 

  24. Dutta, D. et al. Recruitment of calcineurin to the TCR positively regulates T cell activation. Nat. Immunol. 18, 196–204 (2017). This work reports that calcineurin binds LCK and affects its affinity towards ZAP70, influencing downstream signalling.

    Article  PubMed  CAS  Google Scholar 

  25. Sjolin-Goodfellow, H. et al. The catalytic activity of the kinase ZAP-70 mediates basal signaling and negative feedback of the T cell receptor pathway. Sci. Signal. 8, ra49 (2015).

    Article  CAS  Google Scholar 

  26. Couture, C. et al. Regulation of the Lck SH2 domain by tyrosine phosphorylation. J. Biol. Chem. 271, 24880–24884 (1996).

    Article  PubMed  CAS  Google Scholar 

  27. Soula, M. et al. Anti-CD3 and phorbol ester induce distinct phosphorylated sites in the SH2 domain of p56lck. J. Biol. Chem. 268, 27420–27427 (1993).

    PubMed  CAS  Google Scholar 

  28. Granum, S. et al. The kinase Itk and the adaptor TSAd change the specificity of the kinase Lck in T cells by promoting the phosphorylation of Tyr192. Sci. Signal. 7, ra118 (2014).

    Article  PubMed  CAS  Google Scholar 

  29. Courtney, A. H. et al. A phosphosite within the SH2 domain of Lck regulates its activation by CD45. Mol. Cell 67, 498–511.e6 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Pelosi, M. et al. Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck. J. Biol. Chem. 274, 14229–14237 (1999).

    Article  PubMed  CAS  Google Scholar 

  31. Wu, J., Zhao, Q., Kurosaki, T. & Weiss, A. The Vav binding site (Y315) in ZAP-70 is critical for antigen receptor-mediated signal transduction. J. Exp. Med. 185, 1877–1882 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Di Bartolo, V. et al. Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling. J. Biol. Chem. 274, 6285–6294 (1999).

    Article  PubMed  Google Scholar 

  33. Williams, B. L. et al. Phosphorylation of Tyr319 in ZAP-70 is required for T cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation. EMBO J. 18, 1832–1844 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Klammt, C. et al. T cell receptor dwell times control the kinase activity of Zap70. Nat. Immunol. 16, 961–969 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Katz, Z. B., Novotna, L., Blount, A. & Lillemeier, B. F. A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli. Nat. Immunol. 18, 86–95 (2017). This article describes a new ‘catch-and-release’ model in which catalytically active ZAP70 is released from the TCR to the plasma membrane for signal propagation.

    Article  PubMed  CAS  Google Scholar 

  36. Shah, N. H. et al. An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor. Elife 5, e20105 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Yang, M. et al. K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8(+) T cell activation. Nat. Immunol. 16, 1253–1262 (2015).

    Article  PubMed  CAS  Google Scholar 

  38. Mikhailik, A. et al. A phosphatase activity of Sts-1 contributes to the suppression of TCR signaling. Mol. Cell 27, 486–497 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. San Luis, B., Sondgeroth, B., Nassar, N. & Carpino, N. Sts-2 is a phosphatase that negatively regulates zeta-associated protein (ZAP)-70 and T cell receptor signaling pathways. J. Biol. Chem. 286, 15943–15954 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hu, H. et al. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J. Exp. Med. 213, 399–414 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Houtman, J. C. et al. Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1. Nat. Struct. Mol. Biol. 13, 798–805 (2006).

    Article  PubMed  CAS  Google Scholar 

  42. Su, X. et al. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352, 595–599 (2016). This paper describes a new in vitro model system to decipher the different LAT clusters and their role in T cell activation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. Huang, W. Y. et al. Phosphotyrosine-mediated LAT assembly on membranes drives kinetic bifurcation in recruitment dynamics of the Ras activator SOS. Proc. Natl Acad. Sci. USA 113, 8218–8223 (2016).

    Article  PubMed  CAS  Google Scholar 

  45. Kortum, R. L. et al. The ability of Sos1 to oligomerize the adaptor protein LAT is separable from its guanine nucleotide exchange activity in vivo. Sci. Signal. 6, ra99 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  47. Pircher, H., Rohrer, U. H., Moskophidis, D., Zinkernagel, R. M. & Hengartner, H. Lower receptor avidity required for thymic clonal deletion than for effector T cell function. Nature 351, 482–485 (1991).

    Article  PubMed  CAS  Google Scholar 

  48. Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

    Article  PubMed  CAS  Google Scholar 

  49. Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat. Immunol. 10, 1162–1169 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Davey, G. M. et al. Preselection thymocytes are more sensitive to T cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Oh-hora, M. Calcium signaling in the development and function of T-lineage cells. Immunol. Rev. 231, 210–224 (2009).

    Article  PubMed  CAS  Google Scholar 

  52. Lo, W. L., Donermeyer, D. L. & Allen, P. M. A voltage-gated sodium channel is essential for the positive selection of CD4(+) T cells. Nat. Immunol. 13, 880–887 (2012). By using an in vitro system to detect tuning molecules involved in positive and negative T cell selection, this study identifies a VGSC essential for CD4 + T cell selection.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Wang, D. et al. Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nat. Immunol. 13, 560–568 (2012).

    Article  PubMed  CAS  Google Scholar 

  54. Liang, J. et al. Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. Nat. Commun. 8, 15732 (2017). This article gives the first mechanistic insight into TESPA1-mediated regulation of T cell signalling and development.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zou, Q. et al. T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi. J. Exp. Med. 212, 1323–1336 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).

    Article  PubMed  CAS  Google Scholar 

  57. Schaffert, S. A. et al. mir-181a-1/b-1 modulates tolerance through opposing activities in selection and peripheral T cell function. J. Immunol. 195, 1470–1479 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Theodosiou, A. & Ashworth, A. MAP kinase phosphatases. Genome Biol. 3, reviews3009.1–reviews3009.10 (2002).

    Article  Google Scholar 

  59. Wu, J. et al. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J. Biol. Chem. 281, 11002–11010 (2006).

    Article  PubMed  CAS  Google Scholar 

  60. Salmond, R. J., Brownlie, R. J., Morrison, V. L. & Zamoyska, R. The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Nat. Immunol. 15, 875–883 (2014). This paper shows the important role of the PTPN22 phosphatase in TCR signal regulation and TCR discrimination of high-affinity and low-affinity ligands.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Bottini, N. & Peterson, E. J. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu. Rev. Immunol. 32, 83–119 (2014).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  63. Maine, C. J., Teijaro, J. R., Marquardt, K. & Sherman, L. A. PTPN22 contributes to exhaustion of T lymphocytes during chronic viral infection. Proc. Natl Acad. Sci. USA 113, E7231–E7239 (2016).

    Article  PubMed  CAS  Google Scholar 

  64. Pani, G., Fischer, K. D., Mlinaric-Rascan, I. & Siminovitch, K. A. Signaling capacity of the T cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase. J. Exp. Med. 184, 839–852 (1996).

    Article  PubMed  CAS  Google Scholar 

  65. Zhang, J. et al. Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection. J. Immunol. 163, 3012–3021 (1999).

    PubMed  CAS  Google Scholar 

  66. Plas, D. R. et al. Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling. Science 272, 1173–1176 (1996).

    Article  PubMed  CAS  Google Scholar 

  67. Stephen, T. L., Tikhonova, A., Riberdy, J. M. & Laufer, T. M. The activation threshold of CD4+ T cells is defined by TCR/peptide-MHC class II interactions in the thymic medulla. J. Immunol. 183, 5554–5562 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Johnson, D. J. et al. Shp1 regulates T cell homeostasis by limiting IL-4 signals. J. Exp. Med. 210, 1419–1431 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Martinez, R. J., Morris, A. B., Neeld, D. K. & Evavold, B. D. Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection. Eur. J. Immunol. 46, 2103–2110 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Johnson, A. L. et al. Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat. Immunol. 10, 831–839 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Lesourne, R. et al. Themis, a T cell-specific protein important for late thymocyte development. Nat. Immunol. 10, 840–847 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Fu, G. et al. Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nat. Immunol. 10, 848–856 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Patrick, M. S. et al. Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes. Proc. Natl Acad. Sci. USA 106, 16345–16350 (2009).

    Article  PubMed  Google Scholar 

  74. Kakugawa, K. et al. A novel gene essential for the development of single positive thymocytes. Mol. Cell. Biol. 29, 5128–5135 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Fu, G. et al. Themis sets the signal threshold for positive and negative selection in T cell development. Nature 504, 441–445 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Choi, S. et al. THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1. Nat. Immunol. 18, 433–441 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Choi, S., Cornall, R., Lesourne, R. & Love, P. E. THEMIS: two models, different thresholds. Trends Immunol. 38, 622–632 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Ishikawa, E. et al. Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1. Nat. Commun. 7, 12756 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Azzam, H. S. et al. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188, 2301–2311 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Azzam, H. S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464–5472 (2001).

    Article  PubMed  CAS  Google Scholar 

  81. Wong, P., Barton, G. M., Forbush, K. A. & Rudensky, A. Y. Dynamic tuning of T cell reactivity by self-peptide-major histocompatibility complex ligands. J. Exp. Med. 193, 1179–1187 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Tarakhovsky, A. et al. A role for CD5 in TCR-mediated signal transduction and thymocyte selection. Science 269, 535–537 (1995).

    Article  PubMed  CAS  Google Scholar 

  83. Pena-Rossi, C. et al. Negative regulation of CD4 lineage development and responses by CD5. J. Immunol. 163, 6494–6501 (1999).

    PubMed  CAS  Google Scholar 

  84. Voisinne, G. et al. Co-recruitment analysis of the CBL and CBLB signalosomes in primary T cells identifies CD5 as a key regulator of TCR-induced ubiquitylation. Mol. Syst. Biol. 12, 876 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Smith, K. et al. Sensory adaptation in naive peripheral CD4 T cells. J. Exp. Med. 194, 1253–1261 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. 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  PubMed  CAS  Google Scholar 

  87. Fulton, R. B. et al. The TCR’s sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens. Nat. Immunol. 16, 107–117 (2015).

    Article  PubMed  CAS  Google Scholar 

  88. Mandl, J. N., Monteiro, J. P., Vrisekoop, N. & Germain, R. N. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38, 263–274 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kassiotis, G., Zamoyska, R. & Stockinger, B. Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells. J. Exp. Med. 197, 1007–1016 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Kieper, W. C., Burghardt, J. T. & Surh, C. D. A role for TCR affinity in regulating naive T cell homeostasis. J. Immunol. 172, 40–44 (2004).

    Article  PubMed  CAS  Google Scholar 

  91. Cho, J. H. et al. CD45-mediated control of TCR tuning in naive and memory CD8+ T cells. Nat. Commun. 7, 13373 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Persaud, S. P., Parker, C. R., Lo, W. L., Weber, K. S. & Allen, P. M. Intrinsic CD4+ T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC. Nat. Immunol. 15, 266–274 (2014). This study describes two TCRs that bind with identical affinity to cognate ligand but with different affinity to self peptide–MHC complexes, resulting in differences in CD5 expression and antigen responsiveness.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Orta-Mascaro, M. et al. CD6 modulates thymocyte selection and peripheral T cell homeostasis. J. Exp. Med. 213, 1387–1397 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Li, Y. et al. CD6 as a potential target for treating multiple sclerosis. Proc. Natl Acad. Sci. USA 114, 2687–2692 (2017).

    Article  PubMed  CAS  Google Scholar 

  95. Park, J. H. et al. ‘Coreceptor tuning’: cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat. Immunol. 8, 1049–1059 (2007).

    Article  PubMed  CAS  Google Scholar 

  96. Maile, R. et al. Peripheral “CD8 tuning” dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo. J. Immunol. 174, 619–627 (2005).

    Article  PubMed  CAS  Google Scholar 

  97. Holler, P. D. & Kranz, D. M. Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity 18, 255–264 (2003).

    Article  PubMed  CAS  Google Scholar 

  98. Love, P. E., Lee, J. & Shores, E. W. Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection. J. Immunol. 165, 3080–3087 (2000).

    Article  PubMed  CAS  Google Scholar 

  99. Holst, J. et al. Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity. Nat. Immunol. 9, 658–666 (2008).

    Article  PubMed  Google Scholar 

  100. Hwang, S. et al. Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease. J. Exp. Med. 209, 1781–1795 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Guy, C. S. et al. Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nat. Immunol. 14, 262–270 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Hwang, S. et al. TCR ITAM multiplicity is required for the generation of follicular helper T cells. Nat. Commun. 6, 6982 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Klein, L., Kyewski, B., Allen, P. M. & Hogquist, K. A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat. Rev. Immunol. 14, 377–391 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Basu, R. & Huse, M. Mechanical communication at the immunological synapse. Trends Cell Biol. 27, 241–254 (2017).

    Article  PubMed  Google Scholar 

  105. Lee, M. S. et al. A mechanical switch couples T cell receptor triggering to the cytoplasmic juxtamembrane regions of CD3ζζ. Immunity 43, 227–239 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Pageon, S. V. et al. Functional role of T cell receptor nanoclusters in signal initiation and antigen discrimination. Proc. Natl Acad. Sci. USA 113, E5454–E5463 (2016).

    Article  PubMed  CAS  Google Scholar 

  107. Liu, B., Chen, W., Evavold, B. D. & Zhu, C. Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell 157, 357–368 (2014). This report identifies mechanosensor catch bonds and slip bonds that are determined by the affinity of the peptide–MHC for the TCR.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Cai, E. et al. Visualizing dynamic microvillar search and stabilization during ligand detection by T cells. Science 356, eaal3118 (2017).

    Article  PubMed  CAS  Google Scholar 

  109. Valitutti, S., Muller, S., Cella, M., Padovan, E. & Lanzavecchia, A. Serial triggering of many T cell receptors by a few peptide-MHC complexes. Nature 375, 148–151 (1995).

    Article  PubMed  CAS  Google Scholar 

  110. McKeithan, T. W. Kinetic proofreading in T cell receptor signal transduction. Proc. Natl Acad. Sci. USA 92, 5042–5046 (1995).

    Article  PubMed  CAS  Google Scholar 

  111. Germain, R. N. Computational analysis of T cell receptor signaling and ligand discrimination — past, present, and future. FEBS Lett. 584, 4814–4822 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Mayya, V. & Dustin, M. L. What scales the T cell response? Trends Immunol. 37, 513–522 (2016).

    Article  PubMed  CAS  Google Scholar 

  113. Thien, C. B. & Langdon, W. Y. c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses. Biochem. J. 391, 153–166 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Hu, H. & Sun, S. C. Ubiquitin signaling in immune responses. Cell Res. 26, 457–483 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Emmerich, C. H., Schmukle, A. C. & Walczak, H. The emerging role of linear ubiquitination in cell signaling. Sci. Signal. 4, re5 (2011).

    Article  PubMed  CAS  Google Scholar 

  116. Teh, C. E. et al. Linear ubiquitin chain assembly complex coordinates late thymic T cell differentiation and regulatory T cell homeostasis. Nat. Commun. 7, 13353 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Park, Y. et al. SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat. Immunol. 17, 286–296 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Iwai, K., Fujita, H. & Sasaki, Y. Linear ubiquitin chains: NF-κB signalling, cell death and beyond. Nat. Rev. Mol. Cell Biol. 15, 503–508 (2014).

    Article  PubMed  CAS  Google Scholar 

  119. Damgaard, R. B. et al. The deubiquitinase OTULIN is an essential negative regulator of inflammation and autoimmunity. Cell 166, 1215–1230.e20 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Wang, A. et al. Ubc9 is required for positive selection and late-stage maturation of thymocytes. J. Immunol. 198, 3461–3470 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Wang, X. D. et al. TCR-induced sumoylation of the kinase PKC-theta controls T cell synapse organization and T cell activation. Nat. Immunol. 16, 1195–1203 (2015).

    Article  PubMed  CAS  Google Scholar 

  122. Salek, M. et al. Quantitative phosphoproteome analysis unveils LAT as a modulator of CD3ζ and ZAP-70 tyrosine phosphorylation. PLoS ONE 8, e77423 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Roncagalli, R. et al. Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub. Nat. Immunol. 15, 384–392 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Cao, L. et al. Quantitative phosphoproteomics reveals SLP-76 dependent regulation of PAG and Src family kinases in T cells. PLoS ONE 7, e46725 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Jameson, S. C. & Bevan, M. J. T cell receptor antagonists and partial agonists. Immunity 2, 1–11 (1995).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank R. Bosselut, L. Samelson, A. Weiss and R. Zamoyska for helpful comments and suggestions. This work was supported by the Intramural Research Program of the US Eunice Kennedy Shriver National Institute of Child Health and Human Development (P.E.L., project number 1ZIAHD001803-19) and INSERM, France (R.L.).

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Nature Reviews Immunology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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All authors contributed to researching data for the article, discussing the content and writing, reviewing and editing the manuscript.

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Correspondence to Paul E. Love.

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Glossary

Agonist

A peptide that elicits a fully activating signalling response by the T cell receptor (TCR), as opposed to partial agonists and antagonists, which also bind to the TCR but elicit a partial or no signalling response, respectively. Reviewed in Ref.125.

Immune synapse

(IS). A nanoscale molecular close-contact structure formed at the interface between T cells and antigen-presenting cells or other target cells that consists of cell-surface molecules involved in T cell activation. The IS includes a central supramolecular activation cluster (SMAC), which includes the T cell receptor (TCR), as well as peripheral SMAC and distal SMAC concentric regions that contribute to and coordinate TCR signal transduction. Reviewed in ref.6.

Immunoreceptor tyrosine-based activation motifs

(ITAMs). An ITAM is a semi-conserved dityrosine-containing amino acid sequence (YxxL/Ix(6–8)YxxL/I; where Y = tyrosine, L = leucine, I = isoleucine and x = any amino acid) that is present in the cytoplasmic domain of several activating immune receptors, including the T cell recptor and B cell receptor. Reviewed in ref.7.

Signalosome

An intracellular multiprotein complex that in immune cells is composed of adaptor and effector proteins that coordinate, amplify, propagate and potentially diversify signals from proximal inputs. LAT is a major TCR signalling docking protein that nucleates the assembly of a multiprotein LAT signalosome essential for the activation of the T cell. Reviewed in ref.12.

Microclusters

In biological contexts, microclusters are microscopic (~100 nm to 1 µm) aggregates of molecules (typically proteins) that assemble on or in cells constitutively or in response to signalling-induced activation. Nanoclusters are smaller aggregates that are loosely defined but are presumably <100 nm in diameter. Reviewed in ref.13.

Kinetic segregation

A model for T cell receptor (TCR) signal initiation proposing that size-based exclusion of inhibitory surface molecules (such as CD45) during formation of TCR–pMHC close contacts at the immune synapse creates localized areas that favour TCR signalling. Reviewed in ref.4.

Kinetic proofreading

A model for T cell receptor (TCR) signal propagation that proposes a mechanistic explanation for how differences in the affinity of TCR–pMHC interactions and TCR and/or pMHC on/off rates could be translated into distinct signalling responses. Reviewed in ref.4.

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Gaud, G., Lesourne, R. & Love, P.E. Regulatory mechanisms in T cell receptor signalling. Nat Rev Immunol 18, 485–497 (2018). https://doi.org/10.1038/s41577-018-0020-8

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