Age-dependent changes in the regulatory program of CD8+ Regulatory T cells (CD8+ Tregs)

Abstract Regulatory T cells (Tregs) help maintain the immune homeostasis. Any defect in the Tregs causes dysregulated immune responses that leads to risk of infection, autoimmunity, and cancer. Increased morbidity in the elderly patients is due to age-related changes in the immune system called immune aging. Despite several age-related studies in immune cells, immune aging in CD8+ Tregs are poorly characterized. With the growing number of evidence for the presence of various CD8+ Treg subset, our group has recently discovered that mice with knock out of specific CD8+ Treg subset characterized as CD8+ CD122+ Helios+ developed lethal autoimmune phenotype. To our surprise, the autoimmune phenotype is CD4+ Treg independent which underscores the important role of CD8+ CD122+ Helios+ Tregs in autoimmunity. This study investigated the age-associated changes in the CD8+ CD122+ Helios+ Tregs. We measured the quantitative and phenotypic changes of CD8+ Tregs at homeostasis in young (2 months) and older (12–24 months) mice. Our results demonstrate that at homeostasis, frequency of CD8+ Tregs in total lymphocytes is higher in older mice. Of note, older CD8+ Tregs upregulated the expression of Natural Killer group 2-member protein like NKG2A and NKG2D. We used acute infection model to test the age-related effect of infection/inflammation in the CD8+ Treg. We found that Treg numbers further expanded in older mice during acute infection and functionally superior to young mice. In addition, older CD8+ Tregs exhibited altered metabolic profile which might contribute to the immune senescence. In summary our findings support that CD8+ Treg may contribute to the weakened immune response in the elders.