Abstract
Innate γδ T cells function in the early phase of immune responses. Although innate γδ T cells have often been studied as one homogenous population, they can be functionally classified into effector subsets on the basis of the production of signature cytokines, analogous to adaptive helper T cell subsets. However, unlike the function of adaptive T cells, γδ effector T cell function correlates with genomically encoded T cell antigen receptor (TCR) chains, which suggests that clonal TCR selection is not the main determinant of the differentiation of γδ effector cells. A high-resolution transcriptome analysis of all emergent γδ thymocyte subsets segregated on the basis of use of the TCR γ-chain or δ-chain indicated the existence of three separate subtypes of γδ effector cells in the thymus. The immature γδ subsets were distinguished by unique transcription-factor modules that program effector function.
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 SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Heng, T.S. & Painter, M.W. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).
Ferrick, D.A. et al. Differential production of interferon-γ and interleukin-4 in response to Th1- and Th2-stimulating pathogens by γδ T cells in vivo. Nature 373, 255–257 (1995).
Stark, M.A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).
Hayday, A. & Tigelaar, R. Immunoregulation in the tissues by γδ T cells. Nat. Rev. Immunol. 3, 233–242 (2003).
Berg, L.J. Signalling through TEC kinases regulates conventional versus innate CD8+ T-cell development. Nat. Rev. Immunol. 7, 479–485 (2007).
Lee, Y.J., Jameson, S.C. & Hogquist, K.A. Alternative memory in the CD8 T cell lineage. Trends Immunol. 32, 50–56 (2011).
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).
Martin, B., Hirota, K., Cua, D.J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).
Sutton, C.E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).
Melichar, H.J. et al. Regulation of γδ versus αβ T lymphocyte differentiation by the transcription factor SOX13. Science 315, 230–233 (2007).
O'Brien, R.L. & Born, W.K. γδ T cell subsets: a link between TCR and function? Semin. Immunol. 22, 193–198 (2010).
Azuara, V., Levraud, J.P., Lembezat, M.P. & Pereira, P. A novel subset of adult γδ thymocytes that secretes a distinct pattern of cytokines and expresses a very restricted T cell receptor repertoire. Eur. J. Immunol. 27, 544–553 (1997).
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 gamma. Immunity 29, 90–100 (2008).
Ribot, J.C. 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).
Shires, J., Theodoridis, E. & Hayday, A.C. Biological insights into TCRγδ+ and TCRαβ+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).
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).
Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).
Xiong, N., Kang, C. & Raulet, D.H. Positive selection of dendritic epidermal γδ T cell precursors in the fetal thymus determines expression of skin-homing receptors. Immunity 21, 121–131 (2004).
Bain, G. et al. Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade. Nat. Immunol. 2, 165–171 (2001).
Haks, M.C. et al. Attenuation of γδTCR signaling efficiently diverts thymocytes to the αβ lineage. Immunity 22, 595–606 (2005).
Rothenberg, E.V., Zhang, J. & Li, L. Multilayered specification of the T-cell lineage fate. Immunol. Rev. 238, 150–168 (2010).
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).
Pearce, E.L. et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302, 1041–1043 (2003).
Savage, A.K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008).
Kovalovsky, D. et al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat. Immunol. 9, 1055–1064 (2008).
Laird, R.M., Laky, K. & Hayes, S.M. Unexpected role for the B cell-specific Src family kinase B lymphoid kinase in the development of IL-17-producing γδ T cells. J. Immunol. 185, 6518–6527 (2010).
Kisielow, J., Kopf, M. & Karjalainen, K. SCART scavenger receptors identify a novel subset of adult γδ T cells. J. Immunol. 181, 1710–1716 (2008).
Bauquet, A.T. et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10, 167–175 (2009).
Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).
Maruyama, T. et al. Control of the differentiation of regulatory T cells and TH17 cells by the DNA-binding inhibitor Id3. Nat. Immunol. 12, 86–95 (2011).
Djuretic, I.M. et al. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat. Immunol. 8, 145–153 (2007).
Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).
Weinreich, M.A. et al. KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity 31, 122–130 (2009).
Spits, H. & Di Santo, J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011).
Andrews, D.M. et al. Homeostatic defects in interleukin 18-deficient mice contribute to protection against the lethal effects of endotoxin. Immunol. Cell Biol. 89, 739–746 (2011).
Pappu, B.P. et al. TL1A–DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. J. Exp. Med. 205, 1049–1062 (2008).
Yosef, N. & Regev, A. Impulse control: temporal dynamics in gene transcription. Cell 144, 886–896 (2011).
Bendelac, A., Savage, P.B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).
Felices, M., Yin, C.C., Kosaka, Y., Kang, J. & Berg, L.J. Tec kinase Itk in γδ T cells is pivotal for controlling IgE production in vivo. Proc. Natl. Acad. Sci. USA 106, 8308–8313 (2009).
Verykokakis, M. et al. Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor protein-dependent “innate” γδ T cells. PLoS ONE 5, e9303 (2010).
Pereira, P. & Boucontet, L. Rates of recombination and chain pair biases greatly influence the primary γδ TCR repertoire in the thymus of adult mice. J. Immunol. 173, 3261–3270 (2004).
Kuhns, M.S. & Davis, M.M. Disruption of extracellular interactions impairs T cell receptor-CD3 complex stability and signaling. Immunity 26, 357–369 (2007).
Bruno, L., Fehling, H.J. & von Boehmer, H. The ab T cell receptor can replace the γδ receptor in the development of γδ lineage cells. Immunity 5, 343–352 (1996).
Baldwin, T.A., Sandau, M.M., Jameson, S.C. & Hogquist, K.A. The timing of TCR alpha expression critically influences T cell development and selection. J. Exp. Med. 202, 111–121 (2005).
Passoni, L. et al. Intrathymic d selection events in γδ cell development. Immunity 7, 83–95 (1997).
Livák, F., Tourigny, M., Schatz, D.G. & Petrie, H.T. Characterization of TCR gene rearrangements during adult murine T cell development. J. Immunol. 162, 2575–2580 (1999).
Aliahmad, P., de la Torre, B. & Kaye, J. Shared dependence on the DNA-binding factor TOX for the development of lymphoid tissue-inducer cell and NK cell lineages. Nat. Immunol. 11, 945–952 (2010).
Jin, Y., Xia, M., Sun, A., Saylor, C.M. & Xiong, N. CCR10 is important for the development of skin-specific γδ T cells by regulating their migration and location. J. Immunol 185, 5723–5731 (2010).
Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R.M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001).
Lustig, B. et al. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol. Cell. Bio. 22, 1184–1193 (2002).
Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277–290 (2001).
Acknowledgements
We thank M. Mohrs (Trudeau Institute) for IL-4–GFP reporter mice; H. Birchmeier (Max-Delbrück-Center for Molecular Medicine Berlin) for Axin2 reporter mice; V. Lefebvre (Cleveland Clinic) for Sox5 reporter mice; K. Rock (University of Massachusetts Medical School) for Ctsl−/− mice; E. Huseby (University of Massachusetts Medical School) for Cd74−/− mice; S. Davis (Harvard Medical School) for the ConsolidateProbeSets module and PopulationDistances PCA program; A. Hayday (King's College, London) for anti-Vδ1 (17D1); members of the ImmGen Consortium for discussions; the ImmGen core team (M. Painter, J. Ericson and S. Davis) for help with data generation and processing; and eBioscience, Affymetrix and Expression Analysis for support of the ImmGen Project. Core resources supported by the Diabetes Endocrinology Research Center (DK32520) were used. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R24 AI072073 to the ImmGen group, and CA100382 to J.K.).
Author information
Authors and Affiliations
Consortia
Contributions
K.E.S. sorted cell subsets; K.N., N.M., K.E.S. and C.C.Y. did follow-up experiments and analyzed data; G.M., T.V. and K.N. did the studies of M. tuberculosis; H.K. supervised the studies of M. tuberculosis; N.X. provided reagents and cells from a mutant strain; N.R.C. and M.B.B. generated the gene-expression profiles of NKT cell subsets; L.J.B. provided reagents and shared data used in the interpretation of some results; K.N. analyzed gene-expression data; and J.K. and K.N. designed studies and wrote the paper.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–6, Tables 1–12 and Notes 1–2 (PDF 12610 kb)
Supplementary Notes 1
Notes 1 (PDF 3371 kb)
Supplementary Notes 2
Notes 2 (XLS 426 kb)
Rights and permissions
About this article
Cite this article
Narayan, K., Sylvia, K., Malhotra, N. et al. Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes. Nat Immunol 13, 511–518 (2012). https://doi.org/10.1038/ni.2247
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.2247