Terminal effector CD8 T cells defined by an IKZF2⁺IL-7R^- transcriptional signature express FcγRIIIA, expand in HIV infection, and mediate potent HIV-specific antibody-dependent cellular cytotoxicity

HIV-1 infection expands large populations of late-stage differentiated CD8 T cells that may persist long after viral escape from TCR recognition. In this study, we investigated whether such CD8 T cell populations can perform unconventional innate-like antiviral effector functions. Chronic untreated HIV-1 infection was associated with elevated numbers of CD45RA⁺CD57⁺ terminal effector CD8 T cells expressing FcγRIIIA (CD16). The FcγRIIIA⁺ CD8 T cells displayed a distinctive transcriptional profile between conventional CD8 T cells and NK cells, characterized by high levels of IKZF2 and low expression of IL7R. This transcriptional profile translated into a distinct NKp80⁺ IL-7Rα^- surface phenotype with high expression of the Helios transcription factor. Interestingly, the FcγRIIIA⁺ CD8 T cells mediated HIV-specific Ab-dependent cellular cytotoxicity (ADCC) activity at levels comparable with NK cells on a per cell basis. The FcγRIIIA⁺ CD8 T cells were highly activated in a manner that correlated positively with expansion of the CD8 T cell compartment and with plasma levels of soluble mediators of antiviral immunity and inflammation such as IP-10, TNF, IL-6, and TNFRII. The frequency of FcγRIIIA⁺ CD8 T cells persisted as patients initiated suppressive antiretroviral therapy, although their activation levels declined. These data indicate that terminally differentiated effector CD8 T cells acquire enhanced innate cell-like characteristics during chronic viral infection and suggest that HIVspecific ADCC is a function CD8 T cells use to target HIV-infected cells. Furthermore, as the FcγRIIIA⁺ CD8 T cells persist in treatment, they contribute significantly to the ADCC-capable effector cell pool in patients on antiretroviral therapy.