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    T Cells upon InfectionProducing or IL-17Sizes of Murine IFN-

    Receptor Signals Selectively Control the Pool Cutting Edge: Adaptive Versus Innate

    Silva-SantosDecalf, Joo P. Simas, Adrian C. Hayday and BrunoMlanie Wencker, Natacha Gonalves-Sousa, Jrmie Julie C. Ribot, Miguel Chaves-Ferreira, Francisco d'Orey,

    http://www.jimmunol.org/content/185/11/6421doi: 10.4049/jimmunol.1002283October 2010;

    2010; 185:6421-6425; Prepublished online 29J Immunol

    MaterialSupplementary

    3.DC1http://www.jimmunol.org/content/suppl/2010/10/29/jimmunol.100228

    Referenceshttp://www.jimmunol.org/content/185/11/6421.full#ref-list-1

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  • Cutting Edge: Adaptive Versus Innate Receptor SignalsSelectively Control the Pool Sizes of Murine IFN-g orIL-17Producing gd T Cells upon InfectionJulie C. Ribot,*, Miguel Chaves-Ferreira,*,1,2 Francisco dOrey,*,2 Melanie Wencker,,x

    Natacha Goncalves-Sousa ,*, Jeremie Decalf ,* Joao P. Simas,* Adrian C. Hayday ,,x

    and Bruno Silva-Santos*,

    gd T lymphocytes are commonly viewed as embracingproperties of both adaptive and innate immunity. Con-tributing to this is their responsiveness to pathogenproducts, either with or without the involvement ofthe TCR and its coreceptors. This study clarifies thisparadoxical behavior by showing that these two modesof responsiveness are the properties of two discrete setsof murine lymphoid gd T cells. Thus, MyD88 defi-ciency severely impaired the response to malaria infec-tion of CD27(2), IL-17Aproducing gd T cells, but notof IFN-gproducing gd cells. Instead, the latter com-partment was severely contracted by ablating CD27,which synergizes with TCRgd in the induction of anti-apoptotic mediators and cell cycle-promoting genesin CD27(+), IFN-gsecreting gd T cells. Hence, in-nate versus adaptive receptors differentially controlthe peripheral pool sizes of discrete proinflammatorygd T cell subsets during immune responses to in-fection. The Journal of Immunology, 2010, 185:64216425.

    Immunosurveillance in the lymphoid system and in pe-ripheral tissues involves key nonredundant contributionsby gd T cells (1, 2). The widespread implication of gd

    T cells is often attributed to the cells rapid and abundantproduction of IFN-g in mice and in humans (35). However,gd T cells are also a critical source of IL-17A (referred tohereafter as IL-17) in animal models of infection (68) orautoimmune disorders (912). There is therefore a pressingneed to understand what signals regulate the activation andfunctional response of gd T cells.Although our ignorance of most TCRgd ligands confounds

    the full dissection of peripheral gd T cell activation, some gd

    T cells have been shown to respond in vivo to innate receptorligands, notably those for the activating NKG2D receptor(13). This concept was recently extended by reports of TCR-independent stimulation of IL-17 production by IL-1b plusIL-23 (12) and TLR2 or Dectin-1 ligands (14). Collectively,these data have raised the question of the relative importanceof innate immunity-associated receptors versus the somaticallyrecombined TCR and its accessory receptors for the activationof gd T cells in vivo.We have investigated this key question by employing mouse

    infection models, coupled with our recently described classi-fication of thymic and peripheral gd T cell populations (15).We show that for the IFN-gproducing, CD27+ gd (gd27+)subset, CD27 costimulation synergizes with the TCR toprovide survival and proliferative signals that determine theirexpansion upon viral or parasitic infection in vivo. By con-trast, the peripheral pool size of IL-17producing gd T cells,which lack CD27 expression (gd272), depends on TLR/MyD88-dependent innate immune signals during malariainfection. Thus, discrete functional subsets of gd T cells canbe differentially controlled by adaptive and innate immunereceptors.

    Materials and MethodsMice

    All mice were adults 410 wk of age. C57BL/6 (B6), B6.Thy1.1, B6.TCRa-deficient, B6.TCRd-deficient mice were obtained from The Jackson Labo-ratory (Bar Harbor, ME). B6.CD27-deficient mice (16) were a kind gift fromDr. Jannie Borst (The Netherlands Cancer Institute, Amsterdam, TheNetherlands). Mice were bred and maintained in the specific pathogen-freeanimal facilities of Instituto de Medicina Molecular (Lisbon, Portugal),Instituto Gulbenkian de Ciencia (Oeiras, Portugal), and Cancer Research UK(London, U.K.). All experiments involving animals were performed incompliance with the relevant laws and institutional guidelines and have beenapproved by the local ethics committees.

    *Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa,Lisboa; Instituto Gulbenkian de Ciencia, Oeiras, Portugal; London Research Institute,Cancer Research UK, Lincolns Inn Fields; and xDepartment of Immunobiology, KingsCollege School of Medicine, Guys Hospital, London, United Kingdom

    1Current address: INSERM U1020, Necker Institute, Paris, France.

    2M.C.-F. and F.d. contributed equally to this work.

    Received for publication July 9, 2010. Accepted for publication October 4, 2010.

    This work was supported by an installation grant from the European Molecular BiologyOrganization (to B.S.-S.), Grants PTDC/SAU-MII/104158/2008 (to B.S.-S.) andPTDC/SAU-MII/099314/2008 (to J.P.S.) from Fundacao para a Ciencia e Tecnologia,and the Wellcome Trust (to A.C.H. and M.W.).

    Address correspondence and reprint requests to Dr. Bruno Silva-Santos, Instituto deMedicina Molecular, Faculdade de Medicina, Avenue Prof. Egas Moniz, 1649-028Lisboa, Portugal. E-mail address: bssantos@fm.ul.pt

    The online version of this article contains supplemental material.

    Abbreviations used in this paper: LN, lymph node; MuHV-4, murid herpesvirus-4; NS,nonstimulated; PAM, Pam3CysSerLys4; PbA, Plasmodium berghei ANKA; PEC, perito-neal cavity; sCD70, soluble rCD70; WT, wild-type.

    Copyright 2010 by TheAmerican Association of Immunologists, Inc. 0022-1767/10/$16.00

    www.jimmunol.org/cgi/doi/10.4049/jimmunol.1002283

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  • mAbs

    Anti-mouse mAbs specific for TCRd (GL3), IFN-g (XMG1.2), CD3(145.2C11), and Vg4 (UC3-10A6) were purchased from BD Pharmingen (SanDiego, CA). Anti-CD27 (LG.7F9), CD19 (eBio1D3), IL-17A (eBio17B7),CD11b (M1/70), and CD11c (N418) mAbs were purchased from eBioscience(San Diego, CA). Anti-Vg1 (2.11) mAb was a kind gift from Pablo Pereira(Institut Pasteur, Paris, France).

    Flow cytometry

    All FACS-based assays were performed as previously described (15). Cells weresorted on an FACSAria (BD Biosciences, San Jose, CA) and analyzed onFACSCanto or FACSCalibur (BD Biosciences).

    Cell culture and in vitro assays

    Cells were cultured as described (15) and stimulated with anti-CD3 mAb,either plate-bound (1 or 10 mg/ml) or soluble (0.5 mg/ml), in the presence of105 mitomycin C-treated (Sigma-Aldrich, St. Louis, MO) splenocytes. Whereindicated, the following reagents were added to the medium: soluble rCD70(kindly provided by Dr. Jannie Borst) or LPS from Salmonella MinnesotaR595 (10 mg/ml; Alexis Biochemicals, Plymouth Meeting, PA).

    Immunoblotting

    Cells were lysed in RIPA buffer complemented with a complete ProteaseInhibitor Cocktail (Roche Mini Tablet, Roche Applied Science, Burgess Hill,U.K.). Total protein lysates were boiled in sample loading buffer (LDS,Invitrogen, Carlsbad, CA) containing 100 mM DTT. Proteins were subjectedto electrophoresis using NuPage 412% Bis-Tris precasted gels (Invitrogen)and transferred onto a polyvinylidene fluoride membrane (GE Healthcare,Piscataway, NJ). Membranes were stained with rabbit anti-p100/p52 (4882,Cell Signaling Technology, Beverly, MA), mouse anti-GAPDH (MAB374,Millipore, Bedford, MA), donkey anti-rabbit IgG (31458, Thermo Scientific,Waltham, MA), or goat anti-mouse IgG + IgM (31446, Thermo Scientific).Proteins were detec