Inhibition of phosphoantigen-mediated gammadelta T-cell proliferation by CD4+ CD25+ FoxP3+ regulatory T cells.
Tumour growth promotes the expansion of CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) which suppress various arms of immune responses and might therefore contribute to tumour immunosurveillance. In this study, we found an inverse correlation between circulating Treg frequencies and phosphoantigen-induced gammadelta T-cell proliferation in cancer patients, which prompted us to address the role of Tregs in controlling the gammadelta T-cell arm of innate immune responses. In vitro, human Treg-peripheral blood mononuclear cell (PBMC) co-cultures strongly inhibited phosphoantigen-induced proliferation of gammadelta T cells and depletion of Tregs restored the impaired phosphoantigen-induced gammadelta T-cell proliferation of cancer patients. Tregs did not suppress other effector functions of gammadelta T cells such as cytokine production or cytotoxicity. Our experiments indicate that Tregs do not mediate their suppressive activity via a cell-cell contact-dependent mechanism, but rather secrete a soluble non-proteinaceous factor, which is independent of known soluble factors interacting with amino acid depletion (e.g. arginase-diminished arginine and indolamine 2,3-dioxygenase-diminished tryptophan) or nitric oxide (NO) production. However, the proliferative activity of alphabeta T cells was not affected by this cell-cell contact-independent suppressive activity induced by Tregs. In conclusion, these findings indicate a potential new mechanism by which Tregs can specifically suppress gammadelta T cells and highlight the strategy of combining Treg inhibition with subsequent gammadelta T-cell activation to enhance gammadelta T cell-mediated immunotherapy.
Kunzmann
Volker
V
University of Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany. kunzmann_v@medizin.uni-wuerzburg.de
Kimmel
Brigitte
B
Herrmann
Thomas
T
Einsele
Hermann
H
Wilhelm
Martin
M
D000941:Antigens / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D011756:Diphosphates; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007113:Immunity, Innate; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007959:Lymphocyte Culture Test, Mixed; D009369:Neoplasms / Q000276:immunology*; D010750:Phosphoproteins / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000941:Antigens; D011756:Diphosphates; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C429553:bromohydrin pyrophosphate
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