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 cytomegalovirus (CMV), and CX3CR1+ CD8 Tmem are enriched for a putatively immunosenescent CD57+CD28- phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+ CD8 Tmem in vitro, whereas TCR stimulation leads to their death. IL-15-driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15-induced proliferation requires STAT5 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.