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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hogquist, K.A., Baldwin, T.A. & Jameson, S.C. Central tolerance: learning self-control in the thymus. Nat. Rev. Immunol. 5, 772–782 (2005).
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).
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.
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.
Garcia, K.C. et al. A closer look at TCR germline recognition. Immunity 36, 887–888, author reply 889–890 (2012).
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).
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).
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).
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).
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).
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).
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).
Mathis, D. & Benoist, C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).
Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).
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).
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).
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).
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).
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).
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).
Bajoghli, B. et al. Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138, 186–197 (2009).
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).
Gascoigne, N.R. & Palmer, E. Signaling in thymic selection. Curr. Opin. Immunol. 23, 207–212 (2011).
Wang, D. et al. Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nat. Immunol. 13, 560–568 (2012).
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).
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).
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).
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).
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).
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.
Staton, T.L. et al. Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472, 105–109 (2011).
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).
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).
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).
Li, Q.J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).
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).
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).
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).
Azzam, H.S. et al. Fine tuning of TCR signaling by CD5. J. Immunol. 166, 5464–5472 (2001).
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).
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).
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).
Hsieh, C.S., Lee, H.M. & Lio, C.W. Selection of regulatory T cells in the thymus. Nat. Rev. Immunol. 12, 157–167 (2012).
Huynh, A., Zhang, R. & Turka, L.A. Signals and pathways controlling regulatory T cells. Immunol. Rev. 258, 117–131 (2014).
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).
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).
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).
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).
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).
Bautista, J.L. et al. Intraclonal competition limits the fate determination of regulatory T cells in the thymus. Nat. Immunol. 10, 610–617 (2009).
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.
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).
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).
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).
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).
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.
Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).
Konkel, J.E. et al. Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat. Immunol. 12, 312–319 (2011).
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).
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.
Pobezinsky, L.A. et al. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 13, 569–578 (2012).
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).
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).
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.
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.
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).
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).
Surh, C.D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).
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).
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).
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).
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).
Starr, T.K., Jameson, S.C. & Hogquist, K.A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).
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).
Smith, K. et al. Sensory adaptation in naive peripheral CD4 T cells. J. Exp. Med. 194, 1253–1261 (2001).
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).
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).
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).
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).
Nitta, T. et al. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32, 29–40 (2010).
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).
Krogsgaard, M., Juang, J. & Davis, M.M. A role for “self” in T-cell activation. Semin. Immunol. 19, 236–244 (2007).
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).
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.
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
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.2938
This article is cited by
-
B cell-reactive triad of B cells, follicular helper and regulatory T cells at homeostasis
Cell Research (2024)
-
The endogenous repertoire harbors self-reactive CD4+ T cell clones that adopt a follicular helper T cell-like phenotype at steady state
Nature Immunology (2023)
-
A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function
Nature Immunology (2023)
-
I-Ag7 β56/57 polymorphisms regulate non-cognate negative selection to CD4+ T cell orchestrators of type 1 diabetes
Nature Immunology (2023)
-
Complex regulatory effects of gut microbial short-chain fatty acids on immune tolerance and autoimmunity
Cellular & Molecular Immunology (2023)