IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population

Abstract

Vγ9Vδ2 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-γ-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 Vγ9Vδ2 T cells and promote their differentiation into cells with regulatory functions. Here, we demonstrated that activation of Vγ9Vδ2 T cells isolated from healthy donors and cultured in the presence of IL-21 favors the emergence of a subpopulation of Vγ9Vδ2 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 Vγ9Vδ2 T cells. We also showed, in a syngeneic mouse tumor model, the existence of a tumor-infiltrating γδ 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 Vγ9Vδ2 T cells. Altogether, these data indicate that IL-21 promotes Vγ9Vδ2 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 γδ T cell anti-tumor functions.

Vγ9Vδ2 T Cells in the Bone Marrow of Myeloma Patients: A Paradigm of Microenvironment-Induced Immune Suppression

“…Vγ9Vδ2 T cells with regulatory functions have initially been described by Casetti et al ( 68 ), who reported the in vitro induction of FOXP3 + regulatory Vγ9Vδ2 T cells after pAg stimulation in the presence of TGF-β1 and IL-15. Other groups have confirmed the emergence of regulatory/suppressor Vγ9Vδ2 T cells as a consequence of pAg activation in the presence of selected cytokines ( 69 , 70 ). Ma et al have reported an increased proportion of regulatory Vγ9Vδ2 T cells in the PB of MM patients which could suppress antimyeloma immune responses with the same efficiency of conventional Tregs ( 71 ).…”

Pro-tumor γδ T Cells in Human Cancer: Polarization, Mechanisms of Action, and Implications for Therapy

“…We demonstrated that this subset can synthetize adenosine through CD73 enzymatic activity, and produces the suppressive cytokine IL-10 and the chemokine IL-8 (also known as CXCL8) that is involved in the recruitment of polymorphonuclear leukocytes (PMN)-MDSCs. This CD73+ cell subpopulation can suppress the T cell immune response directly in an adenosine-and IL-10-dependent manner, and indirectly by impairing DC antigen presentation (61). We then extended these observations to Vδ1 T cells.…”

“…For example, IL-21 enhances IL-10 production by regulatory B cells and their proliferation. Similarly, our group recently found that IL-21 is implicated in the polarization of human Vγ9Vδ2 T cells and Vδ1 T cells toward a regulatory phenotype (30,61). We isolated a subpopulation of CD73+ regulatory Vγ9Vδ2 T cells following their expansion in the presence of IL-21.…”

Suppressive activity of Vδ2+ γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength

“…To further investigate the role of CD28 stimulation with respect to the induction of suppressive function of Vδ2 + T cells, we analyzed freshly isolated untouched Vδ2 + T cells (purity > 98%, contaminating cells were in the lymphocyte gate in forward versus side scatter (FSC vs SSC) and CD14 negative, thus unlikely monocytes, Supplementary Figure S8) cultivated in wells immobilized with anti-CD28, or anti-TCRγδ or both mAbs and then co-cultured them with autologous T cells stimulated with anti-CD3 mAb (OKT3). Different to in vivo situation where T cell proliferation is dependent on a second signal T cell proliferation solely by OKT3 was already proven in vitro in previous literatures in different settings [51][52][53][54]. Figure 5b illustrates the representative data from one of three donor cultures.…”