Activated-memory T cells influence naïve T cell fate: a noncytotoxic function of human CD8 T cells

T cells are endowed with the capacity to sense their environment including other T cells around them. They do so to set their numbers and activation thresholds. This form of regulation has been well-studied within a given T cell population – i.e., within the naïve or memory pool; however, less is known about the cross-talk between T cell subsets. Here, we tested whether memory T cells interact with and influence surrounding naïve T cells. We report that human naïve CD8 T cells (T N ) undergo phenotypic and transcriptional changes in the presence of autologous activated-memory CD8 T cells (T Mem ). Following in vitro co-culture with activated central memory cells (T CM ), ~3% of the T N acquired activation/memory canonical markers (CD45RO and CD95) in an MHC-I dependent-fashion. Using scRNA-seq, we also observed that ~3% of the T N acquired an activated/memory signature, while ~84% developed a unique activated transcriptional profile hybrid between naïve and activated memory. Pseudotime trajectory analysis provided further evidence that T N with an activated/memory or hybrid phenotype were derived from T N . Our data reveal a non-cytotoxic function of T Mem with potential to activate autologous T N into the activated/memory pool. These findings may have implications for host-protection and autoimmunity that arises after vaccination, infection or transplantation. Human activated memory CD8 T cells develop a non-cytotoxic function and influence the fate of autologous naïve CD8 T cells where they acquire an activated/memory state and a hybrid state between naïve and activated memory.