Identification of a glycosphingolipid+ immune regulatory innate-like CD8 T-cell network in old mice

The reciprocal decline in naive (TN) and increase in virtual (TVM) and true memory (TTM) CD8 T-cell frequencies upon aging is incompletely understood. We established the glycosphingolipid asialo-GM1 (AsGM1) marker present on >70% of TVM/TTM and 5-15% TN to target their immune-regulatory and homeostatic potential. We identified a novel AsGM1+ old CD8 TN-subset that was related to antigen-experienced AsGM1+ CD8 TTM and showed an initial immune-regulatory (Pdcd1, Il10) gene expression signature. The program for AsGM1+ CD8 T-subsets was imprinted genetically in young and old hematopoietic stem cells that reconstitute young and old donor-type immune systems in lymphophenic RAG1-/- mice within 16 weeks, respectively. However, antibody-mediated depletion of AsGM1+ T cells in old mice revealed a disturbed recovery of CD8 TVM resulting in a rejuvenated T-subset composition and T-cell priming capacity upon DNA-vaccination. Old CD8 TVM and IL10+ PD-1+ TTM exerted immune-regulatory functions and suppressed CD3/CD28-mediated activation of TN in vitro. Glycosphingolipids thus are attractive to identify and target novel T-subsets. RNA-seq was performed using CD8 T cell subpopulations from young and old C57BL/6J mice