IL-27 enhances cytokine secretion by TIGIT+ HIVGag-specific T cells

Abstract

Abstract In chronic HIV infection, HIV-specific T cells have diminished effector function and fail to control/eliminate the viral reservoirs. HIV-specific T cells and latently HIV infected T cells express checkpoint receptors suggesting that therapeutic strategies improving T cell function and targeting the reservoir will be required to treat HIV infection. IL-27, a member of the IL-6/IL-12 cytokine superfamily, can be considered as such agent because of its anti-viral properties and immune modulatory functions. IL-27 signaling activates mainly Signal Transducer and Activator of Transcription (STAT) 1 and 3. IL-27 can inhibit HIV replication, however, its immunomodulatory functions in T cells are largely unknown. In this study, we hypothesized that IL-27 promotes pro-inflammatory properties enhancing HIV-specific T cell immunity. We found that IL-27 enhanced STAT1 activation in T cell subsets from people living with HIV (PLWH). Moreover, the RNA-Seq analysis showed that IL-27 stimulation induced global transcriptional changes that overlapped with both IFNα and IL-6 signaling. We also determined that the T cells response to IL-27 stimulation were enriched in genes associated with IFN/STAT1 signaling pathways in PLWH and healthy donors. In addition, overnight in vitro stimulation with IL-27 upregulated expression of CD69 and T-bet in CD4 and CD8 T cells. Accordingly, IL-27 increased IFN-ɣ and TNF-αsecretion by TIGIT+ HIVGag specific CD4 and CD8 T cells. The previously described anti-viral properties and these newly immunomodulatory features of IL-27 in HIV-specific T cell function suggest its potential therapeutic use in HIV cure strategies.