Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15

HIV infection is associated with an increase in the proportion of activated CD8(+) memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8(+) Tmem in people living with HIV (PLWH) is dependent on coinfection with human CMV, and CX3CR1(+)CD8(+) Tmem are enriched for a putatively immunosenescent CO57(+)C1328(-) phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1(+)VD57(+)CD8(+) Tmem in vitro, whereas T cell receptor stimulation leads to their death. IL-15-driven survival is dependent on STATS and Bcl-2 activity, and IL-15-induced proliferation requires STATS and mTORC1. Thus, we identify mechanistic pathways that could explain how inflammescent CX3CR1(+)CD57(+)CD8(+) Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead end.