Excessive reactive oxygen species attenuated IL-17 production in CD161++ CD8+ T cell subset via repression of FOS in HIV-infected immunological non-responders

Immunological non-responders (INR), distinguished by profound immune dysfunction, fail to achieve immune reconstitution despite receiving antiretroviral therapy (ART). INR experience lower life expectancy and higher rates of morbidity and mortality. CD8+ T cells are crucial in controlling HIV progression. However, the function and underlying mechanisms of CD8+ T cells in immune reconstitution remain poorly elucidated. Single-cell RNA sequencing (scRNA-seq) and TCR sequencing were employed to decipher the heterogeneity of CD8+ T cells from immunological responder (IR) and INR. Flow cytometry was utilized to assess the frequency and phenotype of CD161++ CD8+ T cells, the levels of cytoplasmic reactive oxygen species (cytoROS) and intracellular cytokines. qRT-PCR was performed to quantify the mRNA expression of crucial genes. scRNA-seq revealed a CD8+ T cell cluster defined by high KLRB1 (CD161) expression that was enriched in IR. The depletion of CD161++ CD8+ T cells observed in people living with HIV (PLWH) could not be restored by ART, and the expression of CD161++ CD8+ T cells was higher in IR compared to INR, which correlated with both CD4+ T cell counts and their functional status among PLWH on ART. CD161++ CD8+ T cells manifested less susceptibility to activation, senescence, and exhaustion, along with a unique metabolic signature characterized by upregulated lipid and amino acid, alongside downregulated levels of glycolysis, cytoplasmic reactive oxygen species (cytoROS), and mitochondrial mass. Mechanistically, lower levels of cytoROS maintained the homeostasis of IL-17 production in CD161++ CD8+ T cell subset by regulating FOS in IR. Our findings underscore the association between the CD161++ CD8+ T cell subset and immune reconstitution, providing further insight into the molecular mechanisms underlying their decline during HIV infection. These novel insights offer potential targets for interventions aimed at improving immune reconstitution in PLWH on ART. A subset of CD8+ T cells with higher expression levels of CD161 was strongly associated with both CD4+ T cell counts and their functional status among people living with HIV on ART. CD161++ CD8+ T cells exhibited a distinct metabolic profile, with enhanced lipid and amino acid metabolism but reduced glycolysis, cytoROS production, and mitochondrial mass. Lower levels of cytoROS maintained the presence of CD161++ CD8+ T cells through regulating FOS and potentially contributed to immune reconstitution in IR.