Inhibition of murine gammadelta lymphocyte expansion and effector function by regulatory alphabeta T cells is cell-contact-dependent and sensitive to GITR modulation.
Gammadelta 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 gammadelta-T-cell-based cancer therapies. Thus, the regulation of gammadelta-T-cell activity is of great biological and clinical relevance. Here, we show that murine CD4+CD25+ alphabeta T cells, the vast majority of which express the Treg marker, Foxp3, abolish key effector functions of gammadelta T cells, namely the production of the pro-inflammatory cytokines, IFN-gamma 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 gammadelta T cells, results in the induction of an anergic state in gammadelta 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 gammadelta T cells are regulated.
Gonçalves-Sousa
Natacha
N
Molecular Immunology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Portugal.
Ribot
Julie C
JC
deBarros
Ana
A
Correia
Daniel V
DV
Caramalho
Iris
I
Silva-Santos
Bruno
B
D000818:Animals; D002450:Cell Communication; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse