Cytomegalovirus mediates expansion of IL-15-responsive innate-memory cells with SIV killing function

Interindividual immune variability is driven predominantly by environmental factors, including exposure to chronic infectious agents such as cytomegalovirus (CMV). We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells-and marked expansion of innate-memory CD8(+) T cells. These cells express high levels of NKG2A/C and the IL-2 and IL-15 receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C(+)CD122(+)CD8(+) T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I-deficient K562 targets and prompt IFN-gamma production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1-vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C(+)CD8(+) T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innatememory expansion could be achieved by other vaccine platforms expressing IL-15.

Automated summary

Interindividual immune variability is influenced by environmental factors such as chronic infections like CMV. In young macaques, RhCMV infection led to significant changes in immune cell composition and function, including expansion of innate-memory CD8(+) T cells. Vaccination with RhCMV 68-1 vectors also resulted in expansion of functional CD8 cells capable of inhibiting SIV replication ex vivo, suggesting potential for other vaccines expressing IL-15 to achieve innate-memory expansion.