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CD27 is a thymic determinant of the balance between interferon-γ- and interleukin 17–producing γδ T cell subsets

Abstract

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.

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Figure 1: CD27 expression defines distinct subsets of peripheral γδ T cells.
Figure 2: CD27 expression segregates IFN-γ- versus IL-17-producing γδ cells in naive and malaria-infected mice.
Figure 3: Constitutive expression of IL-17 and RORγt by γδ27− cells.
Figure 4: Both γδ27+ and γδ27− cells originate from common CD27+CD25+ thymic γδ progenitors.
Figure 5: CD27 controls the functional potential of γδ T cells.
Figure 6: CD27 signals regulate the differentiation of γδ thymocytes.

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Acknowledgements

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.).

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Experiments were done by J.C.R. (Figs. 1,2,3,4,5,6), A.d.B. (Figs. 2,4,6), D.J.Pa., J.F.N. and D.J.Pe. (Figs. 4,6), V.P. (Fig. 6b and Table 1), S.J.R. and M.G. (Fig. 3c) and B.S.-S. (Fig. 6c,e); J.B. contributed to designing the research and writing the paper; A.C.H. contributed to designing the research and wrote the paper; D.J.Pe. designed the research (Figs. 3,4,5,6) and wrote the paper; and B.S.-S. designed the research (Figs. 1,2,3,4,5,6) and wrote the paper.

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Correspondence to Bruno Silva-Santos.

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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

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