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Published in: Immunologic Research 1-3/2013

01-03-2013 | Immunology in Colorado

A canonical Vγ4Vδ4+ γδ T cell population with distinct stimulation requirements which promotes the Th17 response

Authors: Christina L. Roark, Yafei Huang, Niyun Jin, M. Kemal Aydintug, Tamara Casper, Deming Sun, Willi K. Born, Rebecca L. O’Brien

Published in: Immunologic Research | Issue 1-3/2013

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Abstract

We previously reported a subset of γδ T cells in mice which preferentially responds following intradermal immunization with collagen in complete Freund’s adjuvant (CFA). These cells express a nearly invariant “canonical” Vγ4Vδ4+ TCR. They are potent producers of IL-17A and promote the development of collagen-induced arthritis. In this study, we report that CFA emulsified with PBS alone (without collagen) is sufficient to induce a strong response of Vγ4Vδ4+ cells in the draining lymph nodes of DBA/1 and C57BL/6 mice and that the TCRs of the elicited Vγ4Vδ4+ cells in both strains heavily favor the canonical sequence. However, although both CFA and incomplete Freund’s adjuvant (which lacks the killed mycobacteria present in CFA) induced Vγ4Vδ4+ γδ T cell to expand, only CFA stimulated them to express IL-17A. The route of immunization was also critical, since intraperitoneal CFA induced only a weak response by these cells, whereas intradermal or subcutaneous CFA strongly stimulated them, suggesting that the canonical CFA-elicited Vγ4Vδ4+ cells are recruited from Vγ4+ γδ T cells normally found in the dermis. Their IL-17A response requires the toll-like receptor adapter protein MyD88, and their activation is enhanced by IFNγ, although αβ T cells need not be present. The CFA-elicited Vγ4Vδ4+ γδ T cells show a cytokine profile different from that of other previously described IL-17-producing γδ T cells. Finally, the Vγ4Vδ4+ subset appears to promote the Th17 αβ T cell response, suggesting its importance in mounting an effective immune response against certain pathogens.
Literature
1.
go back to reference O’Brien RL, Roark CL, Jin N, Aydintug MK, French JD, Chain JL, et al. γδ T cell receptors—functional correlations. Immunol Rev. 2007;215:77–88.PubMedCrossRef O’Brien RL, Roark CL, Jin N, Aydintug MK, French JD, Chain JL, et al. γδ T cell receptors—functional correlations. Immunol Rev. 2007;215:77–88.PubMedCrossRef
2.
go back to reference Hayday AC. γδ T cells: a right time and a right place for a conserved third way of protection. Ann Rev Immunol. 2000;18:975–1026.CrossRef Hayday AC. γδ T cells: a right time and a right place for a conserved third way of protection. Ann Rev Immunol. 2000;18:975–1026.CrossRef
3.
4.
go back to reference Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O’Brien RL. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing γδ T cells. J Immunol. 2007;179:5576–83.PubMed Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O’Brien RL. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing γδ T cells. J Immunol. 2007;179:5576–83.PubMed
5.
go back to reference Gray EE, Suzuki K, Cyster JG. Cutting edge: Identification of a motile IL-17-producing γδ T cell population in the dermis. J Immunol. 2011;186(11):6091–5.PubMedCrossRef Gray EE, Suzuki K, Cyster JG. Cutting edge: Identification of a motile IL-17-producing γδ T cell population in the dermis. J Immunol. 2011;186(11):6091–5.PubMedCrossRef
6.
go back to reference Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity. 2011;35(4):596–610.PubMedCrossRef Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity. 2011;35(4):596–610.PubMedCrossRef
7.
go back to reference Sumaria N, Roediger B, Ng LG, Qin J, Pinto R, Cavanagh LL, et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J Exp Med. 2011;208(3):505–18.PubMedCrossRef Sumaria N, Roediger B, Ng LG, Qin J, Pinto R, Cavanagh LL, et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J Exp Med. 2011;208(3):505–18.PubMedCrossRef
8.
go back to reference Sunaga S, Maki K, Komagata Y, Miyazaki J-I, Ikuta K. Developmentally ordered V-J recombination in mouse T cell receptor γ locus is not perturbed by targeted deletion of the Vγ4 gene. J Immunol. 1997;158:4223–8.PubMed Sunaga S, Maki K, Komagata Y, Miyazaki J-I, Ikuta K. Developmentally ordered V-J recombination in mouse T cell receptor γ locus is not perturbed by targeted deletion of the Vγ4 gene. J Immunol. 1997;158:4223–8.PubMed
9.
go back to reference O’Brien RL, Yin X, Huber SA, Ikuta K, Born WK. Depletion of a γδ T cell subset can increase host resistance to a bacterial infection. J Immunol. 2000;165:6472–9.PubMed O’Brien RL, Yin X, Huber SA, Ikuta K, Born WK. Depletion of a γδ T cell subset can increase host resistance to a bacterial infection. J Immunol. 2000;165:6472–9.PubMed
10.
go back to reference Pereira P, Gerber D, Huang SY, Tonegawa S. Ontogenic development and tissue distribution of Vγ1-expressing γ/δ T lymphocytes in normal mice. J Exp Med. 1995;182:1921–30.PubMedCrossRef Pereira P, Gerber D, Huang SY, Tonegawa S. Ontogenic development and tissue distribution of Vγ1-expressing γ/δ T lymphocytes in normal mice. J Exp Med. 1995;182:1921–30.PubMedCrossRef
11.
go back to reference Dent AL, Matis LA, Hooshmand F, Widacki SM, Bluestone JA, Hedrick SM. Self-reactive γδ T cells are eliminated in the thymus. Nature. 1990;343:714–9.PubMedCrossRef Dent AL, Matis LA, Hooshmand F, Widacki SM, Bluestone JA, Hedrick SM. Self-reactive γδ T cells are eliminated in the thymus. Nature. 1990;343:714–9.PubMedCrossRef
12.
go back to reference Goodman T, LeCorre R, Lefrancois L. A T-cell receptor γδ-specific monoclonal antibody detects a Vγ5 region polymorphism. Immunogenetics. 1992;35:65–8.PubMedCrossRef Goodman T, LeCorre R, Lefrancois L. A T-cell receptor γδ-specific monoclonal antibody detects a Vγ5 region polymorphism. Immunogenetics. 1992;35:65–8.PubMedCrossRef
13.
go back to reference Kubo RT, Born W, Kappler JW, Marrack P, Pigeon M. Characterization of a monoclonal antibody which detects all murine αβ T cell receptors. J Immunol. 1989;142:2736–42.PubMed Kubo RT, Born W, Kappler JW, Marrack P, Pigeon M. Characterization of a monoclonal antibody which detects all murine αβ T cell receptors. J Immunol. 1989;142:2736–42.PubMed
14.
go back to reference Dialynas DP, Quan ZS, Wall KA, Pierres A, Quintans J, Loken MR, et al. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983;131:2445–51.PubMed Dialynas DP, Quan ZS, Wall KA, Pierres A, Quintans J, Loken MR, et al. Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule. J Immunol. 1983;131:2445–51.PubMed
15.
go back to reference Heilig JS, Tonegawa S. T-cell γ gene is allelically but not isotypically excluded and is not required in known functional T-cell subsets. Proc Natl Acad Sci USA. 1987;84:8070–4.PubMedCrossRef Heilig JS, Tonegawa S. T-cell γ gene is allelically but not isotypically excluded and is not required in known functional T-cell subsets. Proc Natl Acad Sci USA. 1987;84:8070–4.PubMedCrossRef
16.
go back to reference Arden B, Clark SP, Kabelitz D, Mak TW. Mouse T-cell receptor variable gene segment families. Immunogenetics. 1995;42:501–30.PubMed Arden B, Clark SP, Kabelitz D, Mak TW. Mouse T-cell receptor variable gene segment families. Immunogenetics. 1995;42:501–30.PubMed
17.
go back to reference Kisielow J, Kopf M, Karjalainen K. SCART scavenger receptors identify a novel subset of adult γδ T cells. J Immunol. 2008;181(3):1710–6.PubMed Kisielow J, Kopf M, Karjalainen K. SCART scavenger receptors identify a novel subset of adult γδ T cells. J Immunol. 2008;181(3):1710–6.PubMed
18.
go back to reference Fink DR, Holm D, Schlosser A, Nielsen O, Latta M, Lozano F, et al. Elevated numbers of SCART1+ γδ T cells in skin inflammation and inflammatory bowel disease. Mol Immunol. 2010;47(9):1710–8.PubMedCrossRef Fink DR, Holm D, Schlosser A, Nielsen O, Latta M, Lozano F, et al. Elevated numbers of SCART1+ γδ T cells in skin inflammation and inflammatory bowel disease. Mol Immunol. 2010;47(9):1710–8.PubMedCrossRef
19.
go back to reference Cui Y, Shao H, Lan C, Nian H, O’Brien RL, Born WK, et al. Major role of γδ T cells in the generation of IL-17 uveitogenic T cells. J Immunol. 2009;183:560–7.PubMedCrossRef Cui Y, Shao H, Lan C, Nian H, O’Brien RL, Born WK, et al. Major role of γδ T cells in the generation of IL-17 uveitogenic T cells. J Immunol. 2009;183:560–7.PubMedCrossRef
20.
go back to reference French JD, Roark CL, Born WK, O’Brien RL. γδ T cell homeostasis is established in competition with αβ T cells and NK cells. Proc Natl Acad Sci USA. 2005;102:14741–6.PubMedCrossRef French JD, Roark CL, Born WK, O’Brien RL. γδ T cell homeostasis is established in competition with αβ T cells and NK cells. Proc Natl Acad Sci USA. 2005;102:14741–6.PubMedCrossRef
21.
go back to reference Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-γ: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–89.PubMedCrossRef Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-γ: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–89.PubMedCrossRef
22.
go back to reference Simonian PL, Wehmann F, Roark CL, Born WK, O’Brien RL, Fontenot AP. γδ T cells protect against lung fibrosis via IL-22. J Exp Med. 2010;207:2239–53.PubMedCrossRef Simonian PL, Wehmann F, Roark CL, Born WK, O’Brien RL, Fontenot AP. γδ T cells protect against lung fibrosis via IL-22. J Exp Med. 2010;207:2239–53.PubMedCrossRef
23.
go back to reference Peterman GM, Spencer C, Sperling AI, Bluestone JA. Role of γδ T cells in murine collagen-induced arthritis. J Immunol. 1993;151:6546–58.PubMed Peterman GM, Spencer C, Sperling AI, Bluestone JA. Role of γδ T cells in murine collagen-induced arthritis. J Immunol. 1993;151:6546–58.PubMed
24.
go back to reference Stockinger B, Veldhoen M. Differentiation and function of Th17 cells. Curr Opin Immunol. 2007;19:281–6.PubMedCrossRef Stockinger B, Veldhoen M. Differentiation and function of Th17 cells. Curr Opin Immunol. 2007;19:281–6.PubMedCrossRef
25.
go back to reference Shibata K, Yamada H, Hara H, Kishihara K, Yoshikai Y. Resident Vδ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J Immunol. 2007;178(7):4466–72.PubMed Shibata K, Yamada H, Hara H, Kishihara K, Yoshikai Y. Resident Vδ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J Immunol. 2007;178(7):4466–72.PubMed
26.
go back to reference Nian H, Shao H, O’Brien RL, Born WK, Kaplan HJ, Sun D. Activated γδ T cells promote the activation of uveitogenic T cells and exacerbate EAU development. Invest Ophthalmol Vis Sci. 2011;52(8):5920–7.PubMedCrossRef Nian H, Shao H, O’Brien RL, Born WK, Kaplan HJ, Sun D. Activated γδ T cells promote the activation of uveitogenic T cells and exacerbate EAU development. Invest Ophthalmol Vis Sci. 2011;52(8):5920–7.PubMedCrossRef
27.
go back to reference Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Ladeville EC, Mills KHG. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–41.PubMedCrossRef Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Ladeville EC, Mills KHG. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–41.PubMedCrossRef
28.
go back to reference Lalor SJ, Dungan LS, Sutton CE, Basdeo SA, Fletcher JM, Mills KH. Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity. J Immunol. 2011;186(10):5738–48.PubMedCrossRef Lalor SJ, Dungan LS, Sutton CE, Basdeo SA, Fletcher JM, Mills KH. Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity. J Immunol. 2011;186(10):5738–48.PubMedCrossRef
29.
go back to reference Asarnow DM, Kuziel WA, Bonyhadi M, Tigelaar RE, Tucker PW, Allison JP. Limited diversity of γδ antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell. 1988;55:837–47.PubMedCrossRef Asarnow DM, Kuziel WA, Bonyhadi M, Tigelaar RE, Tucker PW, Allison JP. Limited diversity of γδ antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell. 1988;55:837–47.PubMedCrossRef
30.
go back to reference Itohara S, Farr AG, Lafaille JJ, Bonneville M, Takagaki Y, Haas W, et al. Homing of a γδ thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature. 1990;343:754–7.PubMedCrossRef Itohara S, Farr AG, Lafaille JJ, Bonneville M, Takagaki Y, Haas W, et al. Homing of a γδ thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature. 1990;343:754–7.PubMedCrossRef
31.
go back to reference Kim CH, Witherden DA, Havran WL. Characterization and TCR variable region gene use of mouse resident nasal γδ T lymphocytes. J Leuk Biol. 2008;84:1259–63.CrossRef Kim CH, Witherden DA, Havran WL. Characterization and TCR variable region gene use of mouse resident nasal γδ T lymphocytes. J Leuk Biol. 2008;84:1259–63.CrossRef
32.
go back to reference Grigoriadou K, Boucontet L, Pereira P. Most IL-4-producing γδ thymocytes of adult mice originate from fetal precursors. J Immunol. 2003;171:2413–20.PubMed Grigoriadou K, Boucontet L, Pereira P. Most IL-4-producing γδ thymocytes of adult mice originate from fetal precursors. J Immunol. 2003;171:2413–20.PubMed
33.
go back to reference Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;131:321–30.CrossRef Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;131:321–30.CrossRef
34.
go back to reference Hamada S, Umemura M, Shiono T, Hara H, Kishihara K, Tanaka K, et al. Importance of murine Vδ1 γδ T cells expressing IFNγ and IL-17A in innate protection against Listeria monocytogenes infection. Immunology. 2008;125:170–7.PubMedCrossRef Hamada S, Umemura M, Shiono T, Hara H, Kishihara K, Tanaka K, et al. Importance of murine Vδ1 γδ T cells expressing IFNγ and IL-17A in innate protection against Listeria monocytogenes infection. Immunology. 2008;125:170–7.PubMedCrossRef
35.
go back to reference Huber SA, Graveline DA, Born WK, O’Brien RL. Cytokine production by Vγ+ T cell subsets is an important factor determining CD4 Th-cell phenotype and susceptibility of BALB/c mice to coxsackievirus B3-induced myocarditis. J Virol. 2001;75:5860–9.PubMedCrossRef Huber SA, Graveline DA, Born WK, O’Brien RL. Cytokine production by Vγ+ T cell subsets is an important factor determining CD4 Th-cell phenotype and susceptibility of BALB/c mice to coxsackievirus B3-induced myocarditis. J Virol. 2001;75:5860–9.PubMedCrossRef
36.
go back to reference Mokuno Y, Matsuguchi T, Takano M, Nishimura H, Washizu J, Ogawa T, et al. Expression of toll-like receptor 2 on γδ T cells bearing invariant Vγ6/Vδ1 induced by Escherichia coli infection in mice. J Immunol. 2000;165(2):931–40.PubMed Mokuno Y, Matsuguchi T, Takano M, Nishimura H, Washizu J, Ogawa T, et al. Expression of toll-like receptor 2 on γδ T cells bearing invariant Vγ6/Vδ1 induced by Escherichia coli infection in mice. J Immunol. 2000;165(2):931–40.PubMed
37.
go back to reference Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010;32(5):692–702.PubMedCrossRef Reynolds JM, Pappu BP, Peng J, Martinez GJ, Zhang Y, Chung Y, et al. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity. 2010;32(5):692–702.PubMedCrossRef
38.
go back to reference Zuo A, Liang D, Shao H, Born WK, Kaplan HJ, Sun D. In vivo priming of IL-17(+) uveitogenic T cells is enhanced by Toll ligand receptor (TLR)2 and TLR4 agonists via γδ T cell activation. Mol Immunol. 2012;50(3):125–33.PubMedCrossRef Zuo A, Liang D, Shao H, Born WK, Kaplan HJ, Sun D. In vivo priming of IL-17(+) uveitogenic T cells is enhanced by Toll ligand receptor (TLR)2 and TLR4 agonists via γδ T cell activation. Mol Immunol. 2012;50(3):125–33.PubMedCrossRef
39.
go back to reference Lin Y, Ritchea S, Logar A, Slight S, Messmer M, Rangel-Moreno J, et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity. 2009;31(5):799–810.PubMedCrossRef Lin Y, Ritchea S, Logar A, Slight S, Messmer M, Rangel-Moreno J, et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity. 2009;31(5):799–810.PubMedCrossRef
40.
go back to reference Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8(4):369–77.PubMedCrossRef Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol. 2007;8(4):369–77.PubMedCrossRef
41.
go back to reference Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008;453(7198):1051–7.PubMedCrossRef Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008;453(7198):1051–7.PubMedCrossRef
Metadata
Title
A canonical Vγ4Vδ4+ γδ T cell population with distinct stimulation requirements which promotes the Th17 response
Authors
Christina L. Roark
Yafei Huang
Niyun Jin
M. Kemal Aydintug
Tamara Casper
Deming Sun
Willi K. Born
Rebecca L. O’Brien
Publication date
01-03-2013
Publisher
Springer-Verlag
Published in
Immunologic Research / Issue 1-3/2013
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-012-8364-9

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