Inhibition of murine γδ lymphocyte expansion and effector function by regulatory αβ T cells is cell-contact-dependent and sensitive to GITR modulation

Authors

  • Natacha Gonçalves-Sousa,

    1. Molecular Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
    2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
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  • Julie C. Ribot,

    1. Molecular Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
    2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
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  • Ana deBarros,

    1. Molecular Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
    2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
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  • Daniel V. Correia,

    1. Molecular Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
    2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
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  • Íris Caramalho,

    1. Instituto Gulbenkian de Ciência, Oeiras, Portugal
    2. Clinical Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
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  • Bruno Silva-Santos

    Corresponding author
    1. Molecular Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal
    2. Instituto Gulbenkian de Ciência, Oeiras, Portugal
    • Molecular Immunology Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal Fax: +351-21-798-51-42
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Abstract

γδ T cells are highly cytolytic lymphocytes that produce large amounts of pro-inflammatory cytokines during immune responses to multiple pathogens. Furthermore, their ability to kill tumor cells has fueled the development of γδ-T-cell-based cancer therapies. Thus, the regulation of γδ-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4+CD25+ αβ T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of γδ T cells, namely the production of the pro-inflammatory cytokines, IFN-γ and IL-17, cytotoxicity, and lymphocyte proliferation in vitro and in vivo. We further show that suppression is dependent on cellular contact between Treg and γδ T cells, results in the induction of an anergic state in γδ lymphocytes, and can be partially reversed by manipulating glucocorticoid-induced TNF receptor-related protein (GITR) signals. Our data collectively dissect a novel mechanism by which the expansion and pro-inflammatory functions of γδ T cells are regulated.

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