Skip to main content
SpringerLink
Log in

TCR/ITK Signaling in Type 1 Regulatory T cells

  • Chapter
  • First Online:
T Regulatory Cells in Human Health and Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1278))

Abstract

Type 1 regulatory T (Tr1) cells can modulate inflammation through multiple direct and indirect molecular and cellular mechanisms and have demonstrated potential for anti-inflammatory therapies. Tr1 cells do not express the master transcription factor of conventional regulatory T cells, Foxp3, but express high levels of the immunomodulatory cytokine, IL-10. IL-2-inducible T-cell kinase (ITK) is conserved between mouse and human and is highly expressed in T cells. ITK signaling downstream of the T-cell receptor (TCR) is critical for T-cell subset differentiation and function. Upon activation by TCR, ITK is critical for Ras activation, leading to downstream activation of MAPKs and upregulation of IRF4, which further enable Tr1 cell differentiation and suppressive function. We summarize here the structure, signaling pathway, and function of ITK in T-cell lineage designation, with an emphasis on Tr1 cell development and function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ahangarani RR, Janssens W, VanderElst L, Carlier V, VandenDriessche T, Chuah M, Weynand B, Vanoirbeek JA, Jacquemin M, Saint-Remy JM (2009) In vivo induction of type 1-like regulatory T cells using genetically modified B cells confers long-term IL-10-dependent antigen-specific unresponsiveness. J Immunol 183:8232–8243

    Article  PubMed  CAS  Google Scholar 

  • Akdis M (2008) T-cell tolerance to inhaled allergens: mechanisms and therapeutic approaches. Expert Opin Biol Ther 8:769–777

    Article  CAS  PubMed  Google Scholar 

  • Andreotti AH, Schwartzberg PL, Joseph RE, Berg LJ (2010) T-cell signaling regulated by the Tec family kinase, Itk. Cold Spring Harb Perspect Biol 2:a002287

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, Burns EJ, Sherr DH, Weiner HL, Kuchroo VK (2010) The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11:854–861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • August A, Ragin MJ (2012) Regulation of T-cell responses and disease by tec kinase Itk. Int Rev Immunol 31:155–165

    Article  CAS  PubMed  Google Scholar 

  • August A, Sadra A, Dupont B, Hanafusa H (1997) Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proc Natl Acad Sci U S A 94:11227–11232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • August A, Fischer A, Hao S, Mueller C, Ragin M (2002) The Tec family of tyrosine kinases in T cells, amplifiers of T cell receptor signals. Int J Biochem Cell Biol 34:1184–1189

    Article  CAS  PubMed  Google Scholar 

  • Au-Yeung BB, Katzman SD, Fowell DJ (2006) Cutting edge: Itk-dependent signals required for CD4+ T cells to exert, but not gain, Th2 effector function. J Immunol 176:3895–3899

    Article  CAS  PubMed  Google Scholar 

  • Bacchetta R, Lucarelli B, Sartirana C, Gregori S, Lupo Stanghellini MT, Miqueu P, Tomiuk S, Hernandez-Fuentes M, Gianolini ME, Greco R et al (2014) Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol 5:16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bennett CL, Brunkow ME, Ramsdell F, O’Briant KC, Zhu Q, Fuleihan RL, Shigeoka AO, Ochs HD, Chance PF (2001) A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-->AAUGAA) leads to the IPEX syndrome. Immunogenetics 53:435–439

    Article  CAS  PubMed  Google Scholar 

  • Berg LJ, Finkelstein LD, Lucas JA, Schwartzberg PL (2005) Tec family kinases in T lymphocyte development and function. Annu Rev Immunol 23:549–600

    Article  CAS  PubMed  Google Scholar 

  • Bergmann C, Strauss L, Wang Y, Szczepanski MJ, Lang S, Johnson JT, Whiteside TL (2008) T regulatory type 1 cells in squamous cell carcinoma of the head and neck: mechanisms of suppression and expansion in advanced disease. Clin Cancer Res 14:3706–3715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bishop AC, Shah K, Liu Y, Witucki L, Kung C, Shokat KM (1998) Design of allele-specific inhibitors to probe protein kinase signaling. Curr Biol 8:257–266

    Article  CAS  PubMed  Google Scholar 

  • Bishop AC, Ubersax JA, Petsch DT, Matheos DP, Gray NS, Blethrow J, Shimizu E, Tsien JZ, Schultz PG, Rose MD et al (2000) A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407:395–401

    Article  CAS  PubMed  Google Scholar 

  • Bohm W, Thoma S, Leithauser F, Moller P, Schirmbeck R, Reimann J (1998) T cell-mediated, IFN-gamma-facilitated rejection of murine B16 melanomas. J Immunol 161:897–908

    CAS  PubMed  Google Scholar 

  • Bohm L, Maxeiner J, Meyer-Martin H, Reuter S, Finotto S, Klein M, Schild H, Schmitt E, Bopp T, Taube C (2015) IL-10 and regulatory T cells cooperate in allergen-specific immunotherapy to ameliorate allergic asthma. J Immunol 194:887–897

    Article  PubMed  CAS  Google Scholar 

  • Brady MT, MacDonald AJ, Rowan AG, Mills KH (2003) Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur J Immunol 33:3448–3457

    Article  CAS  PubMed  Google Scholar 

  • Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73

    Article  CAS  PubMed  Google Scholar 

  • Bunnell SC, Diehn M, Yaffe MB, Findell PR, Cantley LC, Berg LJ (2000) Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade. J Biol Chem 275:2219–2230

    Article  CAS  PubMed  Google Scholar 

  • Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106:R75–R81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clemente-Casares X, Blanco J, Ambalavanan P, Yamanouchi J, Singha S, Fandos C, Tsai S, Wang J, Garabatos N, Izquierdo C et al (2016) Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530:434–440

    Article  CAS  PubMed  Google Scholar 

  • Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, Belz GT, Smyth GK, Busslinger M, Nutt SL, Kallies A (2011) The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12:304–311

    Article  CAS  PubMed  Google Scholar 

  • Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, Bouhnik Y, Nachury M, Brun V, Bastian H, Belmonte N et al (2012) Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology 143(1207–1217):e1202

    Google Scholar 

  • Dombroski D, Houghtling RA, Labno CM, Precht P, Takesono A, Caplen NJ, Billadeau DD, Wange RL, Burkhardt JK, Schwartzberg PL (2005) Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. J Immunol 174:1385–1392

    Article  CAS  PubMed  Google Scholar 

  • Felices M, Falk M, Kosaka Y, Berg LJ (2007) Tec kinases in T cell and mast cell signaling. Adv Immunol 93:145–184

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald DC, Zhang GX, El-Behi M, Fonseca-Kelly Z, Li H, Yu S, Saris CJ, Gran B, Ciric B, Rostami A (2007) Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol 8:1372–1379

    Article  CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    Article  CAS  PubMed  Google Scholar 

  • Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, Locksley RM (1999) Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity 11:399–409

    Article  CAS  PubMed  Google Scholar 

  • Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F et al (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19:739–746

    Article  CAS  PubMed  Google Scholar 

  • Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limon P, Paiva RS, Ching T et al (2015) Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523:221–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gambineri E, Torgerson TR, Ochs HD (2003) Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 15:430–435

    Article  CAS  PubMed  Google Scholar 

  • Gilfillan AM, Rivera J (2009) The tyrosine kinase network regulating mast cell activation. Immunol Rev 228:149–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gol-Ara M, Jadidi-Niaragh F, Sadria R, Azizi G, Mirshafiey A (2012) The role of different subsets of regulatory T cells in immunopathogenesis of rheumatoid arthritis. Arthritis 2012:805875

    Article  PubMed  PubMed Central  Google Scholar 

  • Gomez-Rodriguez J, Sahu N, Handon R, Davidson TS, Anderson SM, Kirby MR, August A, Schwartzberg PL (2009) Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase. Immunity 31:587–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Rodriguez J, Wohlfert EA, Handon R, Meylan F, Wu JZ, Anderson SM, Kirby MR, Belkaid Y, Schwartzberg PL (2014) Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. J Exp Med 211:529–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Rodriguez J, Meylan F, Handon R, Hayes ET, Anderson SM, Kirby MR, Siegel RM, Schwartzberg PL (2016) Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun 7:10857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grasis JA, Browne CD, Tsoukas CD (2003) Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal events induced by the T cell antigen receptor. J Immunol 170:3971–3976

    Article  CAS  PubMed  Google Scholar 

  • Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742

    Article  CAS  PubMed  Google Scholar 

  • Hao S, Qi Q, Hu J, August A (2006) A kinase independent function for Tec kinase ITK in regulating antigen receptor induced serum response factor activation. FEBS Lett 580:2691–2697

    Article  CAS  PubMed  Google Scholar 

  • Haringer B, Lozza L, Steckel B, Geginat J (2009) Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood. J Exp Med 206:1009–1017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Jeong AR, Kannan AK, Huang L, August A (2014) IL-2-inducible T cell kinase tunes T regulatory cell development and is required for suppressive function. J Immunol 193:2267–2272

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Solouki S, Koylass N, Zheng SG, August A (2017) ITK signalling via the Ras/IRF4 pathway regulates the development and function of Tr1 cells. Nat Commun 8:15871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY et al (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34:554–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kannan A, Huang W, Huang F, August A (2012) Signal transduction via the T cell antigen receptor in naive and effector/memory T cells. Int J Biochem Cell Biol 44:2129–2134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kannan AK, Sahu N, Mohanan S, Mohinta S, August A (2013) IL-2-inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-gamma in naive CD4+ T cells. J Allergy Clin Immunol 132(811–820):e811–e815

    Article  CAS  Google Scholar 

  • Kannan A, Lee Y, Qi Q, Huang W, Jeong AR, Ohnigian S, August A (2015) Allele-sensitive mutant, Itkas, reveals that Itk kinase activity is required for Th1, Th2, Th17, and iNKT-cell cytokine production. Eur J Immunol 45:2276–2285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342

    Article  CAS  PubMed  Google Scholar 

  • MacDonald AJ, Duffy M, Brady MT, McKiernan S, Hall W, Hegarty J, Curry M, Mills KH (2002) CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J Infect Dis 185:720–727

    Article  CAS  PubMed  Google Scholar 

  • Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S (2011) Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol 41:1652–1662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mascanfroni ID, Takenaka MC, Yeste A, Patel B, Wu Y, Kenison JE, Siddiqui S, Basso AS, Otterbein LE, Pardoll DM et al (2015) Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat Med 21:638–646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGuirk P, McCann C, Mills KH (2002) Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 195:221–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mfarrej B, Tresoldi E, Stabilini A, Paganelli A, Caldara R, Secchi A, Battaglia M (2017) Generation of donor-specific Tr1 cells to be used after kidney transplantation and definition of the timing of their in vivo infusion in the presence of immunosuppression. J Transl Med 15:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Miller AT, Wilcox HM, Lai Z, Berg LJ (2004) Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet. Immunity 21:67–80

    Article  CAS  PubMed  Google Scholar 

  • Mobs C, Slotosch C, Loffler H, Jakob T, Hertl M, Pfutzner W (2010) Birch pollen immunotherapy leads to differential induction of regulatory T cells and delayed helper T cell immune deviation. J Immunol 184:2194–2203

    Article  PubMed  Google Scholar 

  • Ndure J, Flanagan KL (2014) Targeting regulatory T cells to improve vaccine immunogenicity in early life. Front Microbiol 5:477

    Article  PubMed  PubMed Central  Google Scholar 

  • Okamura T, Fujio K, Sumitomo S, Yamamoto K (2012) Roles of LAG3 and EGR2 in regulatory T cells. Ann Rheum Dis 71(Suppl 2):i96–i100

    Article  PubMed  CAS  Google Scholar 

  • Pedroza-Gonzalez A, Zhou G, Vargas-Mendez E, Boor PP, Mancham S, Verhoef C, Polak WG, Grunhagen D, Pan Q, Janssen H et al (2015) Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Onco Targets Ther 4:e1008355

    Google Scholar 

  • Pellerin L, Jenks JA, Chinthrajah S, Dominguez T, Block W, Zhou X, Noshirvan A, Gregori S, Roncarolo MG, Nadeau KC, Bacchetta R (2018) Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired. J Allergy Clin Immunol 141(202–213):e208

    Google Scholar 

  • Pot C, Apetoh L, Awasthi A, Kuchroo VK (2011) Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol 23:438–445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qi Q, Xia M, Bai Y, Yu S, Cantorna M, August A (2011) Interleukin-2-inducible T cell kinase (Itk) network edge dependence for the maturation of iNKT cell. J Biol Chem 286:138–146

    Article  CAS  PubMed  Google Scholar 

  • Roncarolo MG, Gregori S, Bacchetta R, Battaglia M (2014) Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr Top Microbiol Immunol 380:39–68

    CAS  PubMed  Google Scholar 

  • Sahu N, Mueller C, Fischer A, August A (2008) Differential sensitivity to Itk kinase signals for T helper 2 cytokine production and chemokine-mediated migration. J Immunol 180:3833–3838

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    CAS  PubMed  Google Scholar 

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer EM, Debnath J, Yap G, McVicar D, Liao XC, Littman DR, Sher A, Varmus HE, Lenardo MJ, Schwartzberg PL (1999) Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science 284:638–641

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer EM, Broussard C, Debnath J, Anderson S, McVicar DW, Schwartzberg PL (2000) Tec family kinases modulate thresholds for thymocyte development and selection. J Exp Med 192:987–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schaeffer EM, Yap GS, Lewis CM, Czar MJ, McVicar DW, Cheever AW, Sher A, Schwartzberg PL (2001) Mutation of Tec family kinases alters T helper cell differentiation. Nat Immunol 2:1183–1188

    Article  CAS  PubMed  Google Scholar 

  • Serafini G, Andreani M, Testi M, Battarra M, Bontadini A, Biral E, Fleischhauer K, Marktel S, Lucarelli G, Roncarolo MG, Bacchetta R (2009) Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia. Haematologica 94:1415–1426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shevach EM, McHugh RS, Piccirillo CA, Thornton AM (2001) Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 182:58–67

    Article  CAS  PubMed  Google Scholar 

  • Shokat K, Velleca M (2002) Novel chemical genetic approaches to the discovery of signal transduction inhibitors. Drug Discov Today 7:872–879

    Article  CAS  PubMed  Google Scholar 

  • Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stumhofer JS, Silver JS, Laurence A, Porrett PM, Harris TH, Turka LA, Ernst M, Saris CJ, O’Shea JJ, Hunter CA (2007) Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8:1363–1371

    Article  CAS  PubMed  Google Scholar 

  • Su YW, Zhang Y, Schweikert J, Koretzky GA, Reth M, Wienands J (1999) Interaction of SLP adaptors with the SH2 domain of Tec family kinases. Eur J Immunol 29:3702–3711

    Article  CAS  PubMed  Google Scholar 

  • Takesono A, Finkelstein LD, Schwartzberg PL (2002) Beyond calcium: new signaling pathways for Tec family kinases. J Cell Sci 115:3039–3048

    CAS  PubMed  Google Scholar 

  • Tousa S, Semitekolou M, Morianos I, Banos A, Trochoutsou AI, Brodie TM, Poulos N, Samitas K, Kapasa M, Konstantopoulos D et al (2017) Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses. Proc Natl Acad Sci U S A 114:E2891–E2900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Volz T, Skabytska Y, Guenova E, Chen KM, Frick JS, Kirschning CJ, Kaesler S, Rocken M, Biedermann T (2014) Nonpathogenic bacteria alleviating atopic dermatitis inflammation induce IL-10-producing dendritic cells and regulatory Tr1 cells. J Invest Dermatol 134:96–104

    Article  CAS  PubMed  Google Scholar 

  • Werlen G, Palmer E (2002) The T-cell receptor signalosome: a dynamic structure with expanding complexity. Curr Opin Immunol 14:299–305

    Article  CAS  PubMed  Google Scholar 

  • Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20

    Article  CAS  PubMed  Google Scholar 

  • Zeng H, Zhang R, Jin B, Chen L (2015) Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol Immunol 12:566–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

A.A. received research support from 3M Corporation. W.H. received research support from MegaRobo Technologies Corporation. M.C.M. declares no competing financial interests. Research related to this review topic in the authors’ laboratories was supported in part by grants from the National Institutes of Health (R01AI120701, R01AI138570, R56AI146226, R21AI137822, P20GM130555-6610, R21AI129422, R21AI138497, and R35ES028244 (to Gary Perdew)). M.C.M. is a recipient of the Pathobiological Sciences Graduate Program Fellowship in the School of Veterinary Medicine at the Louisiana State University.

Author information

Authors and Affiliations

  1. Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA

    Michael C. McGee & Weishan Huang

  2. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    Avery August & Weishan Huang

Authors
  1. Michael C. McGee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Avery August
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Weishan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Weishan Huang .

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA

    Song-Guo Zheng

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

McGee, M.C., August, A., Huang, W. (2021). TCR/ITK Signaling in Type 1 Regulatory T cells. In: Zheng, SG. (eds) T Regulatory Cells in Human Health and Diseases. Advances in Experimental Medicine and Biology, vol 1278. Springer, Singapore. https://doi.org/10.1007/978-981-15-6407-9_7

Download citation

Publish with us

Policies and ethics

Search

Navigation