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:

The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function

Nature Immunology volume 15, pages 815–823 (2014)Cite this article

Subjects

Abstract

Self-reactivity was once seen as a potential characteristic of T cells that was eliminated by clonal selection to protect the host from autoimmune pathology. It is now understood that the T cell repertoire is in fact broadly self-reactive, even self-centered. The strength with which a T cell reacts to self ligands and the environmental context in which this reaction occurs influence almost every aspect of T cell biology, from development to differentiation to effector function. Here we highlight recent advances and discoveries that relate to T cell self-reactivity, with a particular emphasis on T cell antigen receptor (TCR) signaling thresholds.

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: TCR sensitivity changes as cells mature from cortical (DP) to medullary (SP) thymocytes.
Figure 2: The anatomic context of TCR signaling is crucial for thymocyte fate.
Figure 3: Self-reactivity establishes the activation potential of naive T cells.

Similar content being viewed by others

References

  1. Hogquist, K.A., Baldwin, T.A. & Jameson, S.C. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5, 772–782 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Stritesky, G.L. et al. Murine thymic selection quantified using a unique method to capture deleted T cells. Proc. Natl. Acad. Sci. USA 110, 4679–4684 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Daley, S.R., Hu, D.Y. & Goodnow, C.C. Helios marks strongly autoreactive CD4+ T cells in two major waves of thymic deletion distinguished by induction of PD-1 or NF-κB. J. Exp. Med. 210, 269–285 (2013).This study reports that helios expression distinguishes cells undergoing positive and negative selection in the thymus. Analogously to the previous study, they analyzed helios expression in Bim deficient mice to define the extent of clonal deletion.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Sinclair, C., Bains, I., Yates, A.J. & Seddon, B. Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system. Proc. Natl. Acad. Sci. USA 110, E2905–E2914 (2013).Sinclair et al . estimate rates of death and differentiation using mathematical analysis of synchronized cohorts of thymocytes developing in an inducible ZAP70 model. Their results suggest an asymmetry in the death rates of class I– and class II–restricted thymocytes, and concur remarkably well with the previous two studies that the majority of cells that start selection fail to complete it.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Garcia, K.C. et al. A closer look at TCR germline recognition. Immunity 36, 887–888, author reply 889–890 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Tikhonova, A.N. et al. αβ T cell receptors that do not undergo major histocompatibility complex-specific thymic selection possess antibody-like recognition specificities. Immunity 36, 79–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Bouneaud, C., Kourilsky, P. & Bousso, P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13, 829–840 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Zehn, D. & Bevan, M.J. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity 25, 261–270 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Chu, H.H., Moon, J.J., Kruse, A.C., Pepper, M. & Jenkins, M.K. Negative selection and peptide chemistry determine the size of naive foreign peptide-MHC class II-specific CD4+ T cell populations. J. Immunol. 185, 4705–4713 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Moon, J.J. et al. Quantitative impact of thymic selection on Foxp3+ and Foxp3− subsets of self-peptide/MHC class II-specific CD4+ T cells. Proc. Natl. Acad. Sci. USA 108, 14602–14607 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Taniguchi, R.T. et al. Detection of an autoreactive T-cell population within the polyclonal repertoire that undergoes distinct autoimmune regulator (Aire)-mediated selection. Proc. Natl. Acad. Sci. USA 109, 7847–7852 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pauken, K.E. et al. Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice. J. Immunol. 191, 4913–4917 (2013).

    Article  CAS  PubMed  Google Scholar 

  13. Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Gray, D.H. et al. The BH3-only proteins Bim and Puma cooperate to impose deletional tolerance of organ-specific antigens. Immunity 37, 451–462 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Hu, Q., Sader, A., Parkman, J.C. & Baldwin, T.A. Bim-mediated apoptosis is not necessary for thymic negative selection to ubiquitous self antigens. J. Immunol. 183, 7761–7767 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Dzhagalov, I.L., Chen, K.G., Herzmark, P. & Robey, E.A. Elimination of self-reactive T cells in the thymus: a timeline for negative selection. PLoS Biol. 11, e1001566 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Au-Yeung, B.B. et al. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Nat. Immunol. 15, 687–694 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. McNeil, L.K., Starr, T.K. & Hogquist, K.A. A requirement for sustained ERK signaling during thymocyte positive selection in vivo. Proc. Natl. Acad. Sci. USA 102, 13574–13579 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Suen, A.Y. & Baldwin, T.A. Proapoptotic protein Bim is differentially required during thymic clonal deletion to ubiquitous versus tissue-restricted antigens. Proc. Natl. Acad. Sci. USA 109, 893–898 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bajoghli, B. et al. Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138, 186–197 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. 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  CAS  PubMed Central  PubMed  Google Scholar 

  23. Gascoigne, N.R. & Palmer, E. Signaling in thymic selection. Curr. Opin. Immunol. 23, 207–212 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. 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  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Melichar, H.J., Ross, J.O., Herzmark, P., Hogquist, K.A. & Robey, E.A. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6, ra92 (2013).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Oh-hora, M. et al. Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. Immunity 38, 881–895 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Ross, J.O. et al. Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and TCR signaling patterns. Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.1408482111 (2014).

  29. Hoffmann, A., Kann, O., Ohlemeyer, C., Hanisch, U.K. & Kettenmann, H. Elevation of basal intracellular calcium as a central element in the activation of brain macrophages (microglia): suppression of receptor-evoked calcium signaling and control of release function. J. Neurosci. 23, 4410–4419 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Fu, G. et al. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504, 441–445 (2013).This study shows that Themis deficiency results in activation-induced death of DP thymocytes that are normally positively selected; supporting the idea that Themis selectively dampens low-affinity TCR signals via recruiting the phosphatase SHP1. Themis deficiency had no effect on responses to high-affinity ligands or on the development of agonist-selected T cell populations.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Staton, T.L. et al. Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472, 105–109 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Sinclair, C. & Seddon, B. Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages. J. Immunol. 192, 5151–5159 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Cowan, J.E. et al. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J. Exp. Med. 210, 675–681 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Dyall, R. & Nikolic-Zugic, J. The final maturation of at least some single-positive CD4hi thymocytes does not require T cell receptor–major histocompatibility complex contact. J. Exp. Med. 190, 757–764 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Ziętara, N. et al. Critical role for miR-181a/b-1 in agonist selection of invariant natural killer T cells. Proc. Natl. Acad. Sci. USA 110, 7407–7412 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  37. 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  CAS  PubMed Central  PubMed  Google Scholar 

  38. 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  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. 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  CAS  PubMed Central  PubMed  Google Scholar 

  41. Xing, Y., Jameson, S.C. & Hogquist, K.A. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. Proc. Natl. Acad. Sci. USA 110, 6979–6984 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lo, W.L., Solomon, B.D., Donermeyer, D.L., Hsieh, C.S. & Allen, P.M. T cell immunodominance is dictated by the positively selecting self-peptide. eLife 3, e01457 (2014).

    Article  PubMed Central  PubMed  Google Scholar 

  43. Hsieh, C.S., Lee, H.M. & Lio, C.W. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12, 157–167 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Huynh, A., Zhang, R. & Turka, L.A. Signals and pathways controlling regulatory T cells. Immunol. Rev. 258, 117–131 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Jordan, M.S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Hsieh, C.S., Zheng, Y., Liang, Y., Fontenot, J.D. & Rudensky, A.Y. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401–410 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Moran, A.E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Lee, H.M., Bautista, J.L., Scott-Browne, J., Mohan, J.F. & Hsieh, C.S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37, 475–486 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Bains, I., van Santen, H.M., Seddon, B. & Yates, A.J. Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. PLoS Comput. Biol. 9, e1003102 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Bautista, J.L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 10, 610–617 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Mahmud, S.A. et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15, 473–481 (2014).This study showed that developing thymocytes having a stronger interaction with self peptide–MHC have higher expression of TNF receptor family members, allowing them to preferentially undergo T reg cell induction by allowing more effective competition for IL-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Konkel, J.E., Jin, W., Abbatiello, B., Grainger, J.R. & Chen, W. Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. Proc. Natl. Acad. Sci. USA 111, E465–E473 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wirnsberger, G., Mair, F. & Klein, L. Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell–intrinsic developmental control. Proc. Natl. Acad. Sci. USA 106, 10278–10283 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Seiler, M.P. et al. Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling. Nat. Immunol. 13, 264–271 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Becker, A.M. et al. Invariant NKT cell development requires a full complement of functional CD3ζ immunoreceptor tyrosine–based activation motifs. J. Immunol. 184, 6822–6832 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Bedel, R. et al. Effective functional maturation of invariant natural killer T cells is constrained by negative selection and T-cell antigen receptor affinity. Proc. Natl. Acad. Sci. USA 111, E119–E128 (2014).Using a TCR engineered to have supraphysiologically high-affinity for CD1d self-lipid ligands, this study shows that i NKT cells can be susceptible to clonal deletion. It also shows that lowering the affinity for CD1d led to poor induction of PLZF and the i NKT lineage, suggesting that i NKT development is constrained by a limited range of affinity.

    Article  CAS  PubMed  Google Scholar 

  57. Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Konkel, J.E. et al. Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat. Immunol. 12, 312–319 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Lai, Y.G. et al. IL-15 promotes survival but not effector function differentiation of CD8+ TCRαβ+ intestinal intraepithelial lymphocytes. J. Immunol. 163, 5843–5850 (1999).

    CAS  PubMed  Google Scholar 

  60. Stritesky, G.L., Jameson, S.C. & Hogquist, K.A. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30, 95–114 (2012).Using Bim-deficient Nur77GFP reporter mice, this study reports that the extent of negative selection is far greater than previously appreciated.

    Article  CAS  PubMed  Google Scholar 

  61. Pobezinsky, L.A. et al. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 13, 569–578 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Takada, K. & Jameson, S.C. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9, 823–832 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Dorfman, J.R., Stefanova, I., Yasutomo, K. & Germain, R.N. CD4+ T cell survival is not directly linked to self-MHC-induced TCR signaling. Nat. Immunol. 1, 329–335 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. 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 report finds that CD5hi naive CD4 T cells show superior intrinsic responsiveness (compared to CD5lo cells), which can be uncoupled from the specificity of TCR engagement. However, this stronger reactivity of the CD5hi population makes them more susceptible to IL-2–driven cell death, limiting the expansion of this population during the primary immune response.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. 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).In this report, the authors show that CD5hi naive T cell exhibit enhanced reactivity during a primary immune response, and introduces the novel concept that TCR affinity for foreign peptide–MHC is directly related to the strength of the interaction with self peptide–MHC.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Takeda, S., Rodewald, H.R., Arakawa, H., Bluethmann, H. & Shimizu, T. MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their long-term life span. Immunity 5, 217–228 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. 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 

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

    Article  CAS  PubMed  Google Scholar 

  69. Martin, B., Becourt, C., Bienvenu, B. & Lucas, B. Self-recognition is crucial for maintaining the peripheral CD4+ T-cell pool in a nonlymphopenic environment. Blood 108, 270–277 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Leignadier, J., Hardy, M.P., Cloutier, M., Rooney, J. & Labrecque, N. Memory T-lymphocyte survival does not require T-cell receptor expression. Proc. Natl. Acad. Sci. USA 105, 20440–20445 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Palmer, M.J., Mahajan, V.S., Chen, J., Irvine, D.J. & Lauffenburger, D.A. Signaling thresholds govern heterogeneity in IL-7 receptor–mediated responses of naive CD8+ T cells. Immunol. Cell Biol. 89, 581–594 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Cho, J.H., Kim, H.O., Surh, C.D. & Sprent, J. T cell receptor–dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32, 214–226 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Starr, T.K., Jameson, S.C. & Hogquist, K.A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Lo, W.L. & Allen, P.M. Self-awareness: how self-peptide/MHC complexes are essential in the development of T cells. Mol. Immunol. 55, 186–189 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. 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  CAS  PubMed  Google Scholar 

  77. Johnson, L.D. & Jameson, S.C. Self-specific CD8+ T cells maintain a semi-naive state following lymphopenia-induced proliferation. J. Immunol. 184, 5604–5611 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Saini, M. et al. Regulation of Zap70 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci. Signal. 3, ra23 (2010).

    Article  PubMed  CAS  Google Scholar 

  79. Takada, K. & Jameson, S.C. Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels. J. Exp. Med. 206, 2253–2269 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32, 29–40 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Weber, K.S. et al. Distinct CD4+ helper T cells involved in primary and secondary responses to infection. Proc. Natl. Acad. Sci. USA 109, 9511–9516 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Krogsgaard, M., Juang, J. & Davis, M.M. A role for “self” in T-cell activation. Semin. Immunol. 19, 236–244 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Gascoigne, N.R., Zal, T., Yachi, P.P. & Hoerter, J.A. Co-receptors and recognition of self at the immunological synapse. Curr. Top. Microbiol. Immunol. 340, 171–189 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Hoerter, J.A. et al. Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC. J. Exp. Med. 210, 1807–1821 (2013).These studies shed new light on the way in which peptide-MHC ligands can act as coagonists in the response to foreign peptide–MHC complexes, though showing that the TCR specificity requirement in recognition of a coagonist depends on both TCR and CD8 coreceptor affinity for the agonist ligand.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by the US National Institutes of Health (PO1 AI35296, RO1 AI088209 and R37 AI39560 to K.A.H., and R01 AI75168 and R37 AI38903 to S.C.J.).

Author information

Authors and Affiliations

  1. Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA

    Kristin A Hogquist & Stephen C Jameson

Authors
  1. Kristin A Hogquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen C Jameson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Kristin A Hogquist or Stephen C Jameson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hogquist, K., Jameson, S. The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function. Nat Immunol 15, 815–823 (2014). https://doi.org/10.1038/ni.2938

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2938

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