| Abstract |
V?9V?2 T cells contribute to the immune response against many tumor types through their direct cytotoxic activity and capacity to regulate the biological functions of other immune cells, such as dendritic cells and IFN-?-producing CD8+ T cells. However, their presence in the tumor microenvironment has also been associated with poor prognosis in breast, colon and pancreatic cancers. Additionally, recent studies demonstrated that cytokines can confer some plasticity to V?9V?2 T cells and promote their differentiation into cells with regulatory functions. Here, we demonstrated that activation of V?9V?2 T cells isolated from healthy donors and cultured in the presence of IL-21 favors the emergence of a subpopulation of V?9V?2 T cells that express the ectonucleotidase CD73 and inhibits T cell proliferation in a CD73/adenosine-dependent manner. This subpopulation produces IL-10 and IL-8 and displays lower effector functions and cytotoxic activity than CD73-negative V?9V?2 T cells. We also showed, in a syngeneic mouse tumor model, the existence of a tumor-infiltrating ?? T cell subpopulation that produces IL-10 and strongly expresses CD73. Moreover, maturation, IL-12 production and induction of antigen-specific T cell proliferation are impaired in DC co-cultured with IL-21-amplified V?9V?2 T cells. Altogether, these data indicate that IL-21 promotes V?9V?2 T cell regulatory functions by favoring the development of an immunosuppressive CD73+ subpopulation. Thus, when present in the tumor microenvironment, IL-21 might negatively impact ?? T cell anti-tumor functions. |
Institut de Recherche en Cancérologie de
