Rapid cell cycling of both circulating and resident memory CD8+T cells driven by common gamma chain-dependent cytokines

Abstract Diverse populations of resident leukocytes live and self-renew within the tissues of the body, but the mechanisms controlling their proliferation are poorly understood. Among these populations are many memory CD8+ T cells, which are found throughout the body and can locally control reinfection. A poor ability of vaccines to elicit stable and appropriate tissue-resident CD8+ T cell populations has likely contributed to long-standing challenges in vaccinating against several important pathogens. The factors required to support TRM proliferation in homeostasis are not well understood. We propose that proliferating TRMs flexibly use the available members of the common gamma chain-(γC)-dependent cytokine family to persist as bystanders during other immune responses. We have found that many γC-dependent cytokines can mediate cell-intrinsic signaling to drive proliferation of both circulating and resident memory CD8+ T cells of known antigen specificities without cognate antigen. Via transcriptional analysis of resting and in vivo cytokine-stimulated TRMs, we are elucidating downstream signaling and the gene expression signature of cytokine-driven TRM proliferation. We have also found that memory CD8+ T cells proliferate similarly in response to exogenous cytokines or unrelated pathogens, consistent with pathogen-elicited γC-dependent cytokine signals driving memory CD8+ T cell proliferation. These data support the concept that TRMs use γC-dependent cytokines produced during infections to support enhanced proliferation, likely to promote their maintenance. Our findings may lead to novel methods to therapeutically enhance TRM immunity.