The production of cytokines such as interferon-γ and interleukin 17 by αβ and γδ T cells influences the outcome of immune responses. Here we show that most γδ T lymphocytes expressed the tumor necrosis factor receptor family member CD27 and secreted interferon-γ, whereas interleukin 17 production was restricted to CD27− γδ T cells. In contrast to the apparent plasticity of αβ T cells, the cytokine profiles of these distinct γδ T cell subsets were essentially stable, even during infection. These phenotypes were established during thymic development, when CD27 functions as a regulator of the differentiation of γδ T cells at least in part by inducing expression of the lymphotoxin-β receptor and genes associated with trans-conditioning and interferon-γ production. Thus, the cytokine profiles of peripheral γδ T cells are predetermined mainly by a mechanism involving CD27.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hayday, A.C. & Pennington, D.J. Key factors in the organized chaos of early T cell development. Nat. Immunol. 8, 137–144 (2007).
Bhandoola, A., von Boehmer, H., Petrie, H.T. & Zuniga-Pflucker, J.C. Commitment and developmental potential of extrathymic and intrathymic T cell precursors: plenty to choose from. Immunity 26, 678–689 (2007).
Laky, K., Fleischacker, C. & Fowlkes, B.J. TCR and Notch signaling in CD4 and CD8 T-cell development. Immunol. Rev. 209, 274–283 (2006).
Roark, C.L., Simonian, P.L., Fontenot, A.P., Born, W.K. & O'Brien, R.L. γδ T cells: an important source of IL-17. Curr. Opin. Immunol. 20, 353–357 (2008).
Vermijlen, D. et al. Distinct cytokine-driven responses of activated blood γδ T cells: insights into unconventional T cell pleiotropy. J. Immunol. 178, 4304–4314 (2007).
Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Lochner, M. et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008).
Lockhart, E., Green, A.M. & Flynn, J.L. IL-17 production is dominated by γδ T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J. Immunol. 177, 4662–4669 (2006).
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. 178, 4466–4472 (2007).
Umemura, M. et al. IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J. Immunol. 178, 3786–3796 (2007).
Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat. Immunol. 9, 1297–1306 (2008).
Yang, Y., Xu, J., Niu, Y., Bromberg, J.S. & Ding, Y. T-bet and Eomesodermin play critical roles in directing T cell differentiation to Th1 versus Th17. J. Immunol. 181, 8700–8710 (2008).
Amsen, D. et al. Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515–526 (2004).
Jensen, K.D. et al. Thymic selection determines γδ T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon γ. Immunity 29, 90–100 (2008).
Born, W.K., Reardon, C.L. & O'Brien, R.L. The function of γδ T cells in innate immunity. Curr. Opin. Immunol. 18, 31–38 (2006).
Pennington, D.J. et al. The inter-relatedness and interdependence of mouse T cell receptor γδ+ and αβ+ cells. Nat. Immunol. 4, 991–998 (2003).
Silva-Santos, B., Pennington, D.J. & Hayday, A.C. Lymphotoxin-mediated regulation of γδ cell differentiation by αβ T cell progenitors. Science 307, 925–928 (2005).
Pennington, D.J. et al. Early events in the thymus affect the balance of effector and regulatory T cells. Nature 444, 1073–1077 (2006).
Borst, J., Hendriks, J. & Xiao, Y. CD27 and CD70 in T cell and B cell activation. Curr. Opin. Immunol. 17, 275–281 (2005).
Gao, Y. et al. γδ T cells provide an early source of interferon γ in tumor immunity. J. Exp. Med. 198, 433–442 (2003).
Roark, C.L. et al. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing γδ T cells. J. Immunol. 179, 5576–5583 (2007).
Romani, L. et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).
Shibata, K. et al. Identification of CD25+ γδ T cells as fetal thymus-derived naturally occurring IL-17 producers. J. Immunol. 181, 5940–5947 (2008).
Ruprecht, C.R. et al. Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia. J. Exp. Med. 201, 1793–1803 (2005).
Vossen, M.T. et al. CD27 defines phenotypically and functionally different human NK cell subsets. J. Immunol. 180, 3739–3745 (2008).
Kisielow, J., Kopf, M. & Karjalainen, K. SCART scavenger receptors identify a novel subset of adult γδ T cells. J. Immunol. 181, 1710–1716 (2008).
Ho, M., Webster, H.K., Tongtawe, P., Pattanapanyasat, K. & Weidanz, W.P. Increased γδ T cells in acute Plasmodium falciparum malaria. Immunol. Lett. 25, 139–141 (1990).
Yanez, D.M., Batchelder, J., van der Heyde, H.C., Manning, D.D. & Weidanz, W.P. γδ T-cell function in pathogenesis of cerebral malaria in mice infected with Plasmodium berghei ANKA. Infect. Immun. 67, 446–448 (1999).
Ramsburg, E., Tigelaar, R., Craft, J. & Hayday, A. Age-dependent requirement for γδ T cells in the primary but not secondary protective immune response against an intestinal parasite. J. Exp. Med. 198, 1403–1414 (2003).
D'Ombrain, M.C., Hansen, D.S., Simpson, K.M. & Schofield, L. γδ-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-γ response to Plasmodium falciparum malaria. Eur. J. Immunol. 37, 1864–1873 (2007).
Pamplona, A. et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13, 703–710 (2007).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).
Eberl, G. & Littman, D.R. Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells. Science 305, 248–251 (2004).
Ciofani, M., Knowles, G.C., Wiest, D.L., von Boehmer, H. & Zuniga-Pflucker, J.C. Stage-specific and differential notch dependency at the αβ and γδ T lineage bifurcation. Immunity 25, 105–116 (2006).
Taghon, T., Yui, M.A., Pant, R., Diamond, R.A. & Rothenberg, E.V. Developmental and molecular characterization of emerging β- and γδ-selected pre-T cells in the adult mouse thymus. Immunity 24, 53–64 (2006).
Hendriks, J. et al. CD27 is required for generation and long-term maintenance of T cell immunity. Nat. Immunol. 1, 433–440 (2000).
Carr, J.M. et al. CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector differentiation. Proc. Natl. Acad. Sci. USA 103, 19454–19459 (2006).
Michel, M.L. et al. Identification of an IL-17-producing NK1.1neg iNKT cell population involved in airway neutrophilia. J. Exp. Med. 204, 995–1001 (2007).
Michel, M.L. et al. Critical role of ROR-γt in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc. Natl. Acad. Sci. USA 105, 19845–19850 (2008).
Lee, Y.K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).
Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).
Bendelac, A., Savage, P.B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).
Zuany-Amorim, C. et al. Requirement for γδ T cells in allergic airway inflammation. Science 280, 1265–1267 (1998).
Ivanov, I.I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).
Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).
Hendriks, J., Xiao, Y. & Borst, J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J. Exp. Med. 198, 1369–1380 (2003).
Nolte, M.A. et al. Immune activation modulates hematopoiesis through interactions between CD27 and CD70. Nat. Immunol. 6, 412–418 (2005).
Tesselaar, K. et al. Expression of the murine CD27 ligand CD70 in vitro and in vivo. J. Immunol. 170, 33–40 (2003).
We thank L. Graça (Instituto de Medicina Molecular), G. Anderson (Institute for Biomedical Research, Medical Research Council), B. Rocha (Hôpital Necker), J. Demengeot (Instituto Gulbenkian de Ciência), M.M. Mota (Instituto de Medicina Molecular) and B. Stockinger (Institute for Biomedical Research, Medical Research Council) for materials and suggestions; D. Littman (New York University) for B6.RORγt-GFP mice; P. Pereira (Institut Pasteur) for fluorescein isothiocyanate–labeled anti-Vγ1; J. van Meerwijk (Institut National pour la Santé et la Recherche Médicale, Toulouse) for anti-CD8 and anti-CD4; A. Al-Shamkhani (University of Southampton School of Medicine) for the fusion protein of CD70 and immunoglobulin; D. Bruno, A. Pamplona, A. Pena, N.G. Sousa, D.V. Correia, M. Ferreira, A.Q. Gomes, J. Coquet, T. Silberzahn, S. Zelenay, M.L. Bergman and M. Monteiro for experimental assistance; A.L. Caetano, P. Hutchinson, M. Soares, R. Gardner, W. Turnbull and G. Warnes for cell sorting; the microarray facility at the Nederlands Kanker Instituut for array development; M. Rebelo and A. Costa for the maintenance of mouse strains; and J. van Meerwijk and P. Romagnoli for critical reading of the manuscript. Supported by the European Molecular Biology Organization (YIP 1440 to B.S.-S.), The Research Advisory Board of St. Bartholomew's and The Royal London Charity (RAB 06/PJ/08 to D.J.Pa. and D.J.Pe.), the Wellcome Trust (A.C.H.), and the Portuguese Ministry of Science (J.C.R., A.d.B. and J.F.N.; and PTDC/BIA-BCM/71663 to B.S.-S.).
About this article
Cite this article
Ribot, J., deBarros, A., Pang, D. et al. CD27 is a thymic determinant of the balance between interferon-γ- and interleukin 17–producing γδ T cell subsets. Nat Immunol 10, 427–436 (2009). https://doi.org/10.1038/ni.1717
Experimental & Molecular Medicine (2021)
Microbiota-dependent expansion of testicular IL-17-producing Vγ6+ γδ T cells upon puberty promotes local tissue immune surveillance
Mucosal Immunology (2021)
Nature Immunology (2021)
Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments
Nature Immunology (2021)
Host-derived lipids orchestrate pulmonary γδ T cell response to provide early protection against influenza virus infection
Nature Communications (2021)