Phosphoantigens overcome human TCRVgamma9+ gammadelta Cell immunosuppression by TGF-beta: relevance for cancer immunotherapy.
Human gammadelta cells expressing TCRVgamma9 are HLA-unrestricted CTLs with high relevance for cancer immunotherapy. Many tumor cell types produce TGF-beta, however, a cytokine strongly immunosuppressive for conventional T CD4, CD8, and NK cells. Whether TGF-beta also inhibits TCRVgamma9+ lymphocytes was unknown. Because phosphoantigens (PAgs), such as bromohydrin pyrophosphate, selectively activate the antitumor functions of TCRVgamma9+ T cells, in this study, we investigated whether TGF-beta modulates these functions. We report that TGF-beta does not block activation of TCRVgamma9+ T cells but inhibits their PAg/IL-2-induced proliferation and maturation into effector cells and finally reduces the cytotoxic activity of these gammadelta T cells when exposed to lymphoma target cells. TGF-beta did not bias their differentiation pattern toward gammadelta Th17 or gammadelta regulatory T cells. Nevertheless, increasing doses of PAg stimulus countered TGF-beta inhibition. So, although TGF-beta impairs TCRVgamma9+ gammadelta cells like other cytolytic lymphocytes, PAg alone or combined to therapeutic mAb has the ability to bypass its immunosuppressive activity.
Capietto
Aude-Hélène
AH
Département d'Oncogenèse et Signalisation, Institut National de la Santé et de la Recherche Médicale, Unité 563, France.
Martinet
Ludovic
L
Cendron
Delphine
D
Fruchon
Séverine
S
Pont
Frédéric
F
Fournié
Jean-Jacques
JJ
D000941:Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D011756:Diphosphates / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
D000941:Antigens; D011756:Diphosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; D016212:Transforming Growth Factor beta; C429553:bromohydrin pyrophosphate