Exploring the Role of T VMCells in Age-Related CD8 +T Cell Dysfunction through ATAC-seq and RNA-seq Analysis

Abstract Virtual memory T (T VM) cells are a unique subset of CD8 +T cells that have both classical memory and innate-like immune function. Unlike other CD8 +T cell subsets, T VMcells are highly dependent on cytokines for their homeostasis and are selectively depleted in mice lacking IL-15. In aged mice and humans, T VMcells acquire T cell receptor-associated defects, which may contribute to the decline in overall CD8 +T cell function seen with aging. T VMcells make up a large proportion of the naive CD8 +T cell pool in aged individuals, making them an ideal target for age-specific therapeutic interventions. In this study, we performed ATAC-seq and RNA-seq analysis on young and aged mouse CD8 +T cell subsets and identified several key signatures associated with age-related dysfunction specifically in T VMcells. These signatures reveal a bifurcation in the aging process whereby memory-phenotype CD8 +T cells are affected differently by the aging environment. The aged-specific T VMsignature is distinct from that of conventional memory CD8 +T cells and results in the upregulation of immunomodulatory molecules such as Fcgr2b, which encodes the low-affinity inhibitory Fcγ receptor. Expression of FcγRIIB on CD8 +T cells has been shown to play a role in suppressing anti-tumor immunity and mitigating graft-versus-host disease. We show that a subset of aged T VMcells upregulate FcγRIIB independently of antigen exposure and are prone to apoptosis in vitro. Blockade of FcγRIIB has been shown to augment CD8 +T cell responses in vivo, making it a potential therapeutic target for restoring function in aged T VMcells. These findings provide insight into the mechanisms of age-related immune dysfunction and potential strategies for targeting T VMcells in the elderly. Supported by grants from NHMRC/ARC