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

Abstract

Inter-individual 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-ɣ 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 innate-memory expansion could be achieved by other vaccine platforms expressing IL-15.

Heterogeneity of circulating CD4+CD8+ double-positive T cells characterized by scRNA-seq analysis and trajectory inference

“…By contrast, part of cluster 6, a very small subset, exhibited high expression of EOMES, suggesting a potential difference in function. Within this cluster, the killer cell-like receptor (KLR) family (e.g., KLRC and KLRB1) 22 and killer cell immunoglobulin-like receptor (KIR) family genes (e.g., KIRD2DL4 and KIR3DL12) 23 were expressed exclusively. Additionally, IL2RB, NCR3, FCER1G, and TYROBP, all of which are associated with innate-like function 23 , were also highly expressed.…”

Oncolytic α-herpesvirus and myeloid-tropic cytomegalovirus cooperatively enhance systemic antitumor responses

“…10b). The rIL15RA/IL15 might be antagonistic to the enhancing effect of mCMV coinfection since it may activate CMV-reactive NK cells 37 . No direct correlation was seen between blood IL12-p70 levels and CR rate (Supplementary Fig.…”

Ablation of Lsd1 induces viral mimicry in thymocytes and promotes the development of innate-memory T cells

“…While conventional memory T cells are induced by TCR stimulation with a foreign antigen, innate-memory T cells were also found to increase in virus infection models, such as H1N1 [42] and rhesus CMV [43]. We considered that the overexpression of EREs in Lsd1-deleted thymocytes was related to the innate-memory phenotype.…”