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Annual Review of Cell and Developmental Biology

Volume 32, 2016

TCR Signal Strength and T Cell Development

Abstract

Thymocyte selection involves the positive and negative selection of the repertoire of T cell receptors (TCRs) such that the organism does not suffer autoimmunity, yet has the benefit of the ability to recognize any invading pathogen. The signal transduced through the TCR is translated into a number of different signaling cascades that result in transcription factor activity in the nucleus and changes to the cytoskeleton and motility. Negative selection involves inducing apoptosis in thymocytes that express strongly self-reactive TCRs, whereas positive selection must induce survival and differentiation programs in cells that are more weakly self-reactive. The TCR recognition event is analog by nature, but the outcome of signaling is not. A large number of molecules regulate the strength of the TCR-derived signal at various points in the cascades. This review discusses the various factors that can regulate the strength of the TCR signal during thymocyte development.

Keyword(s): signaling, T cell development, T cell receptor, Themis, thymus
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2016-10-06
2024-04-18
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Literature Cited

  1. Acuto O, Di Bartolo V, Micheli F. 2008. Tailoring T-cell receptor signals by proximal negative feedback mechanisms. Nat. Rev. Immunol. 8:699–712 [Google Scholar]
  2. Alam SM, Davies GM, Lin CM, Zal T, Nasholds W. et al. 1999. Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands. Immunity 10:227–37 [Google Scholar]
  3. Alam SM, Travers PJ, Wung JL, Nasholds W, Redpath S. et al. 1996. T cell receptor affinity and thymocyte positive selection. Nature 381:616–20 [Google Scholar]
  4. Altan-Bonnet G, Germain RN. 2005. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLOS Biol. 3:e356 [Google Scholar]
  5. Anderson G, Moore NC, Owen JJT, Jenkinson EJ. 1996. Cellular interactions in thymocyte development. Annu. Rev. Immunol. 14:73–99 [Google Scholar]
  6. Ashton-Rickardt PG, Bandeira A, Delaney JR, Van Kaer L, Pircher H. et al. 1994. Evidence for a differential avidity model of T cell selection in the thymus. Cell 76:651–63 [Google Scholar]
  7. Au-Yeung BB, Melichar HJ, Ross JO, Cheng DA, Zikherman J. et al. 2014. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Nat. Immunol. 15:687–94 [Google Scholar]
  8. Azzam HS, DeJarnette JB, Huang K, Emmons R, Park CS. et al. 2001. Fine tuning of TCR signaling by CD5. J. Immunol. 166:5464–72 [Google Scholar]
  9. Azzam HS, Grinberg A, Lui K, Shen H, Shores EW, Love PE. 1998. CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity. J. Exp. Med. 188:2301–11 [Google Scholar]
  10. Balamuth F, Leitenberg D, Unternaehrer J, Mellman I, Bottomly K. 2001. Distinct patterns of membrane microdomain partitioning in Th1 and Th2 cells. Immunity 15:729–38 [Google Scholar]
  11. Basson MA. 2012. Signaling in cell differentiation and morphogenesis. Cold Spring Harb. Perspect. Biol. 4a008151
  12. Beyersdorf N, Braun A, Vogtle T, Varga-Szabo D, Galdos RR. et al. 2009. STIM1-independent T cell development and effector function in vivo. J. Immunol. 182:3390–97 [Google Scholar]
  13. Borgne ML, Ladi E, Dzhagalov I, Herzmark P, Liao YF. et al. 2009. The impact of negative selection on thymocyte migration in the medulla.. Nat. Immunol. 10:823–30 [Google Scholar]
  14. Brockmeyer C, Paster W, Pepp er D, Tan CP, Trudgian DC. et al. 2011. T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component. J. Biol. Chem. 286:7535–47 [Google Scholar]
  15. Brzostek J, Gascoigne NRJ. 2013. Too fast to die. Sci. Signal. 6:pe33 [Google Scholar]
  16. Carter JD, Neel BG, Lorenz U. 1999. The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds. Int. Immunol. 11:1999–2014 [Google Scholar]
  17. Casas J, Brzostek J, Zarnitsyna VI, Hong JS, Wei Q. et al. 2014. Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor. Nat. Commun. 5:5624 [Google Scholar]
  18. Constant SL, Bottomly K. 1997. Induction of TH1 and TH2 CD4+ T cell responses: the alternative approaches. Annu. Rev. Immunol. 15:297–322 [Google Scholar]
  19. Costello PS, Nicolas RH, Watanabe Y, Rosewell I, Treisman R. 2004. Ternary complex factor SAP-1 is required for Erk-mediated thymocyte positive selection. Nat. Immunol. 5:289–98 [Google Scholar]
  20. Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D. et al. 2006. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444:724–29 [Google Scholar]
  21. Dustin ML, Ferguson LM, Chan PY, Springer TA, Golan DE. 1996. Visualization of CD2 interaction with LFA-3 and determination of the two-dimensional dissociation constant for adhesion receptors in a contact area. J. Cell Biol. 132:465–74 [Google Scholar]
  22. Dzhagalov IL, Chen KG, Herzmark P, Robey EA. 2013. Elimination of self-reactive T cells in the thymus: a timeline for negative selection. PLOS Biol. 11:e1001566 [Google Scholar]
  23. Ebert PJ, Jiang S, Xie J, Li QJ, Davis MM. 2009. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat. Immunol. 10:1162–69 [Google Scholar]
  24. Fischer AM, Katayama CD, Pages G, Pouyssegur J, Hedrick SM. 2005. The role of erk1 and erk2 in multiple stages of T cell development. Immunity 23:431–43 [Google Scholar]
  25. Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F. et al. 2013. Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504:441–45 [Google Scholar]
  26. Fu G, Rybakin V, Brzostek J, Paster W, Acuto O, Gascoigne NRJ. 2014. Fine-tuning T cell receptor signaling to control T cell development. Trends Immunol. 35:311–18 [Google Scholar]
  27. Fu G, Vallee S, Rybakin V, McGuire MV, Ampudia J. et al. 2009. Themis controls thymocyte selection through regulation of T cell antigen receptor-mediated signaling. Nat. Immunol. 10:848–56 [Google Scholar]
  28. Fujimoto T, Matsuzaki H, Tanaka M, Shirasawa S. 2013. Tespa1 protein is phosphorylated in response to store-operated calcium entry. Biochem. Biophys. Res. Commun. 434:162–65 [Google Scholar]
  29. Fujimoto T, Miyasaka K, Koyanagi M, Tsunoda T, Baba I. et al. 2009. Altered energy homeostasis and resistance to diet-induced obesity in KRAP-deficient mice. PLOS ONE 4:e4240 [Google Scholar]
  30. Fulton RB, Hamilton SE, Xing Y, Best JA, Goldrath AW. et al. 2015. The TCR's sensitivity to self peptide–MHC dictates the ability of naive CD8+ T cells to respond to foreign antigens. Nat. Immunol. 16:107–17 [Google Scholar]
  31. Garcia KC, Adams JJ, Feng D, Ely LK. 2009. The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat. Immunol. 10:143–47 [Google Scholar]
  32. Gascoigne NRJ. 2001. Positive selection in a Schnurri. Nat. Immunol. 2:989–91 [Google Scholar]
  33. Gascoigne NRJ. 2008. Do T cells need endogenous peptides for activation?. Nat. Rev. Immunol. 8:895–900 [Google Scholar]
  34. Gascoigne NRJ, Acuto O. 2015. THEMIS: a critical TCR signal regulator for ligand discrimination. Curr. Opin. Immunol. 33:86–92 [Google Scholar]
  35. Gascoigne NRJ, Casas J, Brzostek J, Rybakin V. 2011. Initiation of TCR phosphorylation and signal transduction. Front. Immunol. 2:72 [Google Scholar]
  36. Gascoigne NRJ, Fu G. 2012. Tespa1: another gatekeeper for positive selection. Nat. Immunol. 13:530–32 [Google Scholar]
  37. Gascoigne NRJ, Palmer E. 2011. Signaling in thymic selection. Curr. Opin. Immunol. 23:207–12 [Google Scholar]
  38. Gascoigne NRJ, Zal T, Yachi PP, Hoerter JAH. 2010. Co-receptors and recognition of self at the immunological synapse. Curr. Top Microbiol. Immunol. 340:171–89 [Google Scholar]
  39. Girao C, Hu Q, Sun J, Ashton-Rickardt PG. 1997. Limits to the differential avidity model of T cell selection in the thymus. J. Immunol. 159:4205–11 [Google Scholar]
  40. Gommeaux J, Gregoire C, Nguessan P, Richelme M, Malissen M. et al. 2009. Thymus-specific serine protease regulates positive selection of a subset of CD4+ thymocytes. Eur. J. Immunol. 39:956–64 [Google Scholar]
  41. Gronski MA, Boulter JM, Moskophidis D, Nguyen LT, Holmberg K. et al. 2004. TCR affinity and negative regulation limit autoimmunity. Nat. Med. 10:1234–39 [Google Scholar]
  42. Henao-Mejia J, Williams A, Goff LA, Staron M, Licona-Limon P. et al. 2013. The microRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell ontogenesis and lymphocyte development and homeostasis. Immunity 38:984–97 [Google Scholar]
  43. Hoerter JAH, Brzostek J, Artyomov MN, Abel SM, Casas J. et al. 2013. Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC. J. Exp. Med. 210:1807–21 [Google Scholar]
  44. Hogquist KA, Gavin MA, Bevan MJ. 1993. Positive selection of CD8+ T cells induced by major histocompatibility complex binding peptides in fetal thymic organ culture. J. Exp. Med. 177:1469–73 [Google Scholar]
  45. Hogquist KA, Jameson SC, Bevan MJ. 1995. Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells. Immunity 3:79–86 [Google Scholar]
  46. Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, Carbone FR. 1994. T cell receptor antagonist peptides induce positive selection. Cell 76:17–27 [Google Scholar]
  47. Hogquist KA, Tomlinson AJ, Kieper WC, McGargill MA, Hart MC. et al. 1997. Identification of a naturally occurring ligand for positive selection. Immunity 6:389–99 [Google Scholar]
  48. Holmberg K, Mariathasan S, Ohteki T, Ohashi PS, Gascoigne NRJ. 2003. TCR binding kinetics measured with MHC class I tetramers reveal a positive selecting peptide with relatively high affinity for TCR. J. Immunol. 171:2427–34 [Google Scholar]
  49. Honey K, Nakagawa T, Peters C, Rudensky A. 2002. Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands. J. Exp. Med. 195:1349–58 [Google Scholar]
  50. Huang J, Zarnitsyna VI, Liu B, Edwards LJ, Jiang N. et al. 2010. The kinetics of two-dimensional TCR and pMHC interactions determine T-cell responsiveness. Nature 464:932–36 [Google Scholar]
  51. Huppa JB, Axmann M, Mortelmaier MA, Lillemeier BF, Newell EW. et al. 2010. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature 463:963–67 [Google Scholar]
  52. Jameson SC, Hogquist KA, Bevan MJ. 1994. Specificity and flexibility in thymic selection. Nature 369:750–52 [Google Scholar]
  53. Jiang N, Huang J, Edwards LJ, Liu B, Zhang Y. et al. 2011. Two-stage cooperative T cell receptor–peptide major histocompatibility complex–CD8 trimolecular interactions amplify antigen discrimination. Immunity 34:13–23 [Google Scholar]
  54. Johnson AL, Aravind L, Shulzhenko N, Morgun A, Choi SY. et al. 2009. Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection. Nat. Immunol. 10:831–39 [Google Scholar]
  55. Johnson DJ, Pao LI, Dhanji S, Murakami K, Ohashi PS, Neel BG. 2013. Shp1 regulates T cell homeostasis by limiting IL-4 signals. J. Exp. Med. 210:1419–31 [Google Scholar]
  56. Juang J, Ebert PJ, Feng D, Garcia KC, Krogsgaard M, Davis MM. 2010. Peptide-MHC heterodimers show that thymic positive selection requires a more restricted set of self-peptides than negative selection. J. Exp. Med. 207:1223–34 [Google Scholar]
  57. Kakugawa K, Yasuda T, Miura I, Kobayashi A, Fukiage H. et al. 2009. A novel gene essential for the development of single positive thymocytes. Mol. Cell. Biol. 29:5128–35 [Google Scholar]
  58. Kieback E, Hilgenberg E, Stervbo U, Lampropoulou V, Shen P. et al. 2016. Thymus-derived regulatory T cells are positively selected on natural self-antigen through cognate interactions of high functional avidity. Immunity 44:1114–26 [Google Scholar]
  59. Klein L, Kyewski B, Allen PM, Hogquist KA. 2014. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14:377–91 [Google Scholar]
  60. Krogsgaard M, Juang J, Davis MM. 2007. A role for “self” in T-cell activation. Semin. Immunol. 19:236–44 [Google Scholar]
  61. Krogsgaard M, Li QJ, Sumen C, Huppa JB, Huse M, Davis MM. 2005. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434:238–43 [Google Scholar]
  62. Leitenberg D, Boutin Y, Constant S, Bottomly K. 1998. CD4 regulation of TCR signaling and T cell differentiation following stimulation with peptides of different affinities for the TCR. J. Immunol. 161:1194–203 [Google Scholar]
  63. Lesourne R, Uehara S, Lee J, Song KD, Li L. et al. 2009. Themis, a T cell–specific protein important for late thymocyte development. Nat. Immunol. 10:840–47 [Google Scholar]
  64. Li QJ, Chau J, Ebert PJ, Sylvester G, Min H. et al. 2007. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–61 [Google Scholar]
  65. Liu B, Chen W, Evavold BD, Zhu C. 2014. Accumulation of dynamic catch bonds between TCR and agonist peptide–MHC triggers T cell signaling. Cell 157:357–68 [Google Scholar]
  66. Lo WL, Donermeyer DL, Allen PM. 2012. A voltage-gated sodium channel is essential for the positive selection of CD4+ T cells. Nat. Immunol. 13:880–87 [Google Scholar]
  67. Lo WL, Felix NJ, Walters JJ, Rohrs H, Gross ML, Allen PM. 2009. An endogenous peptide positively selects and augments the activation and survival of peripheral CD4+ T cells. Nat. Immunol. 10:1155–61 [Google Scholar]
  68. Malchow S, Leventhal DS, Lee V, Nishi S, Socci ND, Savage PA. 2016. Aire enforces immune tolerance by directing autoreactive T cells into the regulatory T cell lineage. Immunity 44:1102–13 [Google Scholar]
  69. Mandl JN, Monteiro JP, Vrisekoop N, Germain RN. 2013. T cell–positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38:263–74 [Google Scholar]
  70. Mariathasan S, Zakarian A, Bouchard D, Michie AM, Zúñiga-Pflücker JC, Ohashi PS. 2001. Duration and strength of extracellular signal–regulated kinase signals are altered during positive versus negative thymocyte selection. J. Immunol. 167:4966–73 [Google Scholar]
  71. Marrack P, Scott-Browne JP, Dai S, Gapin L, Kappler JW. 2008. Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu. Rev. Immunol. 26:171–203 [Google Scholar]
  72. Mathis D, Benoist C. 2009. Aire. Annu. Rev. Immunol. 27:287–312 [Google Scholar]
  73. Matsuzaki H, Fujimoto T, Ota T, Ogawa M, Tsunoda T. et al. 2012. Tespa1 is a novel inositol 1,4,5-trisphosphate receptor binding protein in T and B lymphocytes. FEBS Open Biol. 2:255–59 [Google Scholar]
  74. Matsuzaki H, Fujimoto T, Tanaka M, Shirasawa S. 2013. Tespa1 is a novel component of mitochondria-associated endoplasmic reticulum membranes and affects mitochondrial calcium flux. Biochem. Biophys. Res. Commun. 433:322–26 [Google Scholar]
  75. Mayans S, Stepniak D, Palida SF, Larange A, Dreux J. et al. 2014. αβT cell receptors expressed by CD4−CD8αβ− intraepithelial T cells drive their fate into a unique lineage with unusual MHC reactivities. Immunity 41:207–18 [Google Scholar]
  76. McDonald BD, Bunker JJ, Ishizuka IE, Jabri B, Bendelac A. 2014. Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ+CD4−CD8β− intraepithelial lymphocyte lineage. Immunity 41:219–29 [Google Scholar]
  77. McNeil LK, Starr TK, Hogquist KA. 2005. A requirement for sustained ERK signaling during thymocyte positive selection in vivo. PNAS 102:13574–79 [Google Scholar]
  78. Melichar HJ, Ross JO, Herzmark P, Hogquist KA, Robey EA. 2013. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6ra92
  79. Melichar HJ, Ross JO, Taylor KT, Robey EA. 2015. Stable interactions and sustained TCR signaling characterize thymocyte-thymocyte interactions that support negative selection. J. Immunol. 194:1057–61 [Google Scholar]
  80. Moran AE, Holzapfel KL, Xing Y, Cunningham NR, Maltzman JS. et al. 2011. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208:1279–89 [Google Scholar]
  81. Murata S, Sasaki K, Kishimoto T, Niwa S, Hayashi H. et al. 2007. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316:1349–53 [Google Scholar]
  82. Murphy MA, Schnall RG, Venter DJ, Barnett L, Bertoncello I. et al. 1998. Tissue hyperplasia and enhanced T-cell signalling via ZAP-70 in c-Cbl-deficient mice. Mol. Cell. Biol. 18:4872–82 [Google Scholar]
  83. Naeher D, Daniels MA, Hausmann B, Guillaume P, Luescher I, Palmer E. 2007. A constant affinity threshold for T cell tolerance. J. Exp. Med. 204:2553–59 [Google Scholar]
  84. Nakagawa T, Roth W, Wong P, Nelson A, Farr A. et al. 1998. Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus. Science 280:450–53 [Google Scholar]
  85. Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H. 2002. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat. Immunol. 3:1192–99 [Google Scholar]
  86. Naramura M, Kole HK, Hu R-J, Gu H. 1998. Altered thymic positive selection and intracellular signals in Cbl-deficient mice. PNAS 95:15547–52 [Google Scholar]
  87. Niederberger N, Holmberg K, Alam SM, Sakati W, Naramura M. et al. 2003. Allelic exclusion of the TCR α-chain is an active process requiring TCR-mediated signaling and c-Cbl. J. Immunol. 170:4557–63 [Google Scholar]
  88. Nika K, Soldani C, Salek M, Paster W, Gray A. et al. 2010. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32:766–77 [Google Scholar]
  89. Nitta T, Murata S, Sasaki K, Fujii H, Ripen AM. et al. 2010. Thymoproteasome shapes immunocompetent repertoire of CD8+ T cells. Immunity 32:29–40 [Google Scholar]
  90. Oh-Hora M, Komatsu N, Pishyareh M, Feske S, Hori S. et al. 2013. Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. Immunity 38:881–95 [Google Scholar]
  91. Palmer E. 2003. Negative selection—clearing out the bad apples from the T-cell repertoire. Nat. Rev. Immunol. 3:383–91 [Google Scholar]
  92. Palmer E, Naeher D. 2009. Affinity threshold for thymic selection through a T-cell receptor-co-receptor zipper. Nat. Rev. Immunol. 9:207–13 [Google Scholar]
  93. Paster W, Brockmeyer C, Fu G, Simister PC, de Wet B. et al. 2013. GRB2-mediated recruitment of THEMIS to LAT is essential for thymocyte development. J. Immunol. 190:3749–56 [Google Scholar]
  94. Paster W, Bruger AM, Katsch K, Gregoire C, Roncagalli R. et al. 2015. A THEMIS:SHP1 complex promotes T-cell survival. EMBO J. 34:393–409 [Google Scholar]
  95. Patrick MS, Oda H, Hayakawa K, Sato Y, Eshima K. et al. 2009. Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes. PNAS 106:16345–50 [Google Scholar]
  96. Perez-Villar JJ, Whitney GS, Bowen MA, Hewgill DH, Aruffo AA, Kanner SB. 1999. CD5 negatively regulates the T-cell antigen receptor signal transduction pathway: involvement of SH2-containing phosphotyrosine phosphatase SHP-1. Mol. Cell. Biol. 19:2903–12 [Google Scholar]
  97. Persaud SP, Parker CR, Lo WL, Weber KS, Allen PM. 2014. 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. 15:266–74 [Google Scholar]
  98. Plas DR, Williams CB, Kersh GJ, White LS, White JM. et al. 1999. Cutting edge: The tyrosine phosphatase SHP-1 regulates thymocyte positive selection. J. Immunol. 162:5680–84 [Google Scholar]
  99. Pobezinsky LA, Angelov GS, Tai X, Jeurling S, Van Laethem F. et al. 2012. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat. Immunol. 13:569–78 [Google Scholar]
  100. Reinherz EL, Wang JH. 2015. Codification of bidentate pMHC interaction with TCR and its co-receptor. Trends Immunol. 36:300–6 [Google Scholar]
  101. Rogers PR, Croft M. 1999. Peptide dose, affinity, and time of differentiation can contribute to the Th1/Th2 cytokine balance. J. Immunol. 163:1205–13 [Google Scholar]
  102. Roncagalli R, Hauri S, Fiore F, Liang Y, Chen Z. et al. 2014. 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. 15:384–92 [Google Scholar]
  103. Ross JO, Melichar HJ, Au-Yeung BB, Herzmark P, Weiss A, Robey EA. 2014. Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns. PNAS 111:E2550–58 [Google Scholar]
  104. Roybal KT, Mace EM, Clark DJ, Leard AD, Herman A. et al. 2015a. Modest interference with actin dynamics in primary T cell activation by antigen presenting cells preferentially affects lamellal signaling. PLOS ONE 10:e0133231 [Google Scholar]
  105. Roybal KT, Mace EM, Mantell JM, Verkade P, Orange JS, Wulfing C. 2015b. Early signaling in primary T cells activated by antigen presenting cells is associated with a deep and transient lamellal actin network. PLOS ONE 10:e0133299 [Google Scholar]
  106. Saibil SD, Ohteki T, White FM, Luscher M, Zakarian A. et al. 2003. Weak agonist self-peptides promote selection and tuning of virus-specific T cells. Eur. J. Immunol. 33:685–96 [Google Scholar]
  107. Salmond RJ, Filby A, Pirinen N, Magee AI, Zamoyska R. 2011. Mislocalization of Lck impairs thymocyte differentiation and can promote development of thymomas. Blood 117:108–17 [Google Scholar]
  108. Santori FR, Kieper WC, Brown SM, Lu Y, Neubert TA. et al. 2002. Rare, structurally homologous self-peptides promote thymocyte positive selection. Immunity 17:131–42 [Google Scholar]
  109. Sasaki K, Takada K, Ohte Y, Kondo H, Sorimachi H. et al. 2015. Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells. Nat. Commun. 6:7484 [Google Scholar]
  110. Schaffert SA, Loh C, Wang S, Arnold CP, Axtell RC. et al. 2015. mir-181a-1/b-1 modulates tolerance through opposing activities in selection and peripheral T cell function. J. Immunol. 195:1470–79 [Google Scholar]
  111. Sebzda E, Kündig TM, Thomson CT, Aoki K, Mak SY. et al. 1996. Mature T cell reactivity altered by peptide agonist that induces positive selection. J. Exp. Med. 183:1093–104 [Google Scholar]
  112. Sebzda E, Wallace VA, Mayer J, Yeung RSM, Mak TW, Ohashi PS. 1994. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 263:1615–18 [Google Scholar]
  113. Shao H, Wilkinson B, Lee B, Han PC, Kaye J. 1999. Slow accumulation of active mitogen-activated protein kinase during thymocyte differentiation regulates the temporal pattern of transcription factor gene expression. J. Immunol. 163:603–10 [Google Scholar]
  114. Singer A, Adoro S, Park JH. 2008. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat. Rev. Immunol. 8:788–801 [Google Scholar]
  115. Singleton KL, Roybal KT, Sun Y, Fu G, Gascoigne NRJ. et al. 2009. Spatiotemporal patterning during T cell activation is highly diverse. Sci. Signal. 2:ra15 [Google Scholar]
  116. Starr TK, Jameson SC, Hogquist KA. 2003. Positive and negative selection of T cells. Annu. Rev. Immunol. 21:139–76 [Google Scholar]
  117. Staton TL, Lazarevic V, Jones DC, Lanser AJ, Takagi T. et al. 2011. Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472:105–9 [Google Scholar]
  118. Stefanova I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN. 2003. TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat. Immunol. 4:248–54 [Google Scholar]
  119. Stepanek O, Prabhakar AS, Osswald C, King CG, Bulek A. et al. 2014. Coreceptor scanning by the T cell receptor provides a mechanism for T cell tolerance. Cell 159:333–45 [Google Scholar]
  120. Stritesky GL, Jameson SC, Hogquist KA. 2012. Selection of self-reactive T cells in the thymus. Annu. Rev. Immunol. 30:95–114 [Google Scholar]
  121. Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X. et al. 2013. Murine thymic selection quantified using a unique method to capture deleted T cells. PNAS 110:4679–84 [Google Scholar]
  122. Takagi T, Harada J, Ishii S. 2001. Mouse Schnurri-2 is required for positive selection of thymocytes. Immunity 2:1048–53 [Google Scholar]
  123. Tarakhovsky A, Kanner SB, Hombach J, Ledbetter JA, Muller W. et al. 1995. A role for CD5 in TCR-mediated signal transduction and thymocyte selection. Science 269:535–37 [Google Scholar]
  124. Thome M, Duplay P, Guttinger M, Acuto O. 1995. Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex. J. Exp. Med. 181:1997–2006 [Google Scholar]
  125. Tikhonova AN, Van Laethem F, Hanada K, Lu J, Pobezinsky LA. et al. 2012. αβ T cell receptors that do not undergo major histocompatibility complex–specific thymic selection possess antibody-like recognition specificities. Immunity 36:79–91 [Google Scholar]
  126. Van Laethem F, Sarafova SD, Park JH, Tai X, Pobezinsky L. et al. 2007. Deletion of CD4 and CD8 coreceptors permits generation of αβT cells that recognize antigens independently of the MHC. Immunity 27:735–50 [Google Scholar]
  127. Van Laethem F, Tikhonova AN, Pobezinsky LA, Tai X, Kimura MY. et al. 2013. Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326–41 [Google Scholar]
  128. van Panhuys N, Klauschen F, Germain RN. 2014. T-cell-receptor-dependent signal intensity dominantly controls CD4+ T cell polarization in vivo. Immunity 41:63–74 [Google Scholar]
  129. Viret C, Lamare C, Guiraud M, Fazilleau N, Bour A. et al. 2011. Thymus-specific serine protease contributes to the diversification of the functional endogenous CD4 T cell receptor repertoire. J. Exp. Med. 208:3–11 [Google Scholar]
  130. Wang D, Zheng M, Lei L, Ji J, Yao Y. et al. 2012. Tespa1 is involved in late thymocyte development through the regulation of TCR-mediated signaling. Nat. Immunol. 13:560–68 [Google Scholar]
  131. Wang H, Holst J, Woo SR, Guy C, Bettini M. et al. 2010. Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development. EMBO J. 29:1285–98 [Google Scholar]
  132. Werlen G, Hausmann B, Palmer E. 2000. A motif in the αβ T-cell receptor controls positive selection by modulating ERK activity. Nature 406:422–26 [Google Scholar]
  133. Williams CB, Engle DL, Kersh GJ, White JM, Allen PM. 1999. A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor–ligand complex. J. Exp. Med. 189:1531–44 [Google Scholar]
  134. Witt CM, Raychaudhuri S, Schaefer B, Chakraborty AK, Robey EA. 2005. Directed migration of positively selected thymocytes visualized in real time. PLOS Biol. 3:e160 [Google Scholar]
  135. Xiao Y, Qiao G, Tang J, Tang R, Guo H. et al. 2015. Protein tyrosine phosphatase SHP-1 modulates T cell responses by controlling Cbl-b degradation. J. Immunol. 195:4218–27 [Google Scholar]
  136. Xing Y, Ja meson SC, Hogquist KA. 2013. Thymoproteasome subunit-β5T generates peptide-MHC complexes specialized for positive selection. PNAS 110:6979–84 [Google Scholar]
  137. Xu H, Littman DR. 1993. A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 74:633–43 [Google Scholar]
  138. Yachi PP, Ampudia J, Gascoigne NRJ, Zal T. 2005. Nonstimulatory peptides contribute to antigen-induced CD8–T cell receptor interaction at the immunological synapse. Nat. Immunol. 6:785–92 [Google Scholar]
  139. Yachi PP, Ampudia J, Zal T, Gascoigne NRJ. 2006. Altered peptide ligands induce delayed and reduced CD8-TCR interaction—a role for CD8 in distinguishing antigen quality. Immunity 25:203–11 [Google Scholar]
  140. Yachi PP, Lotz C, Ampudia J, Gascoigne NRJ. 2007. T cell activation enhancement by endogenous pMHC acts for both weak and strong agonists but varies with differentiation state. J. Exp. Med. 204:2747–57 [Google Scholar]
  141. Zhang J, Somani AK, Yuen D, Yang Y, Love PE, Siminovitch KA. 1999. Involvement of the SHP-1 tyrosine phosphatase in regulation of T cell selection. J. Immunol. 163:3012–21 [Google Scholar]
  142. Zikherman J, Parameswaran R, Weiss A. 2012. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489:160–64 [Google Scholar]
  143. Zvezdova E, Mikolajczak J, Garreau A, Marcellin M, Rigal L. et al. 2016. Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability. Sci. Signal. 9:ra51 [Google Scholar]
/content/journals/10.1146/annurev-cellbio-111315-125324
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TCR Signal Strength and T Cell Development
Annual Review of Cell and Developmental Biology 32, 327 (2016); https://doi.org/10.1146/annurev-cellbio-111315-125324
/content/journals/10.1146/annurev-cellbio-111315-125324
/content/journals/10.1146/annurev-cellbio-111315-125324
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