Interleukin-18 activates Vg9Vd2+ T cells from HIV+ Individuals: Recovering the Response to Phosphoantigen

Abstract

Gammadelta (gd) T cells, particularly the peripheral blood subset Vg9Vd2, are unconventional lymphocytes that act as strong cytotoxic effectors against both malignant and virus-infected cells. Unlike conventional alpha beta T cells, gd T cells recognize non-peptidic antigens without classical MHC presentation. Most human Vg9Vd2 T cells are stimulated by phosphoantigens related to isopentenyl pyrophosphate (IPP). The Vg9Vd2 subset of human T cells is depleted during HIV disease and not reconstituted after prolonged antiretroviral therapy (ART). Their loss is part of the immunodeficiency syndrome likely linked to increased opportunistic infections or cancer. Our goals are to understand the mechanisms preventing full reconstitution of Vg9Vd2 T cells and discover conditions in HIV+ patients that are limiting the functionality of existing cells. These cells remain incapable of responding to phosphoantigens even while re-gaining responsiveness to aminobisphosphonate drugs including zoledronic acid (Zol). Zol treatment increases stimulatory IPP and promotes secretion of Caspase-1 processed cytokines IL-18 and IL-1β through its effects on the NLRP3 inflammasome. The Vd2 T cell subset was particularly high for IL-18 receptor expression compared to traditional IL-18 targets CD8+ T and natural killer cells. IL-18 stimulation increased proliferation, enhanced the accumulation of effector memory cells, and increased expression of cytotoxic markers in HIV-negative controls. When Vg9Vd2 T cells from HIV+ individuals were stimulated with IPP in the presence of IL-18, there was increased proliferation, accumulation of memory cells, and higher expression of CD56, NKG2D, and CD107a (markers of cytotoxic effector phenotype). IL-18 stimulation specifically expanded the Vg9-JgP+ subset of Vg9Vd2 T cells as is expected for normal responses to phosphoantigen. Interleukin-18 is a potent stimulator of Vg9Vd2 T cell proliferation and effector function. We hope to translate this study to promote recovery of Vd2 T cells in immuno-compromised HIV patients for anti-tumor and anti-viral responses.