Common gamma chain-dependent cytokines drive antigen-independent proliferation of circulating and resident memory CD8+ T cells

Abstract

Abstract Memory CD8+ T cells are found throughout the body and can locally control reinfection at barrier sites. Vaccines often fail to elicit durable tissue-resident memory (TRM) CD8+ T cells, likely contributing to unsuccessful efforts to vaccinate against several important pathogens. TRMs locally self-renew by poorly understood mechanisms; a better understanding of this process could help to enhance TRM immunity. We propose that proliferating TRMs flexibly use available members of the common gamma chain-(γC)-dependent cytokine family to persist and as bystanders during other immune responses. We have found that γC-dependent cytokines can mediate cell-intrinsic signaling to drive proliferation of both circulating and resident memory CD8+ T cells, in contrast to naïve T cells. Using adoptive transfer as well as tetramer staining of endogenous populations, we have confirmed that cytokine-stimulated proliferation of memory T cells of known antigen specificities elicited by different pathogens can occur without cognate antigen. Via bulk and single-cell RNA-Seq of resting and in vivo cytokine-stimulated memory CD8+ T cells, we are elucidating the downstream signature of cytokine-driven TRM proliferation. We have also found that memory CD8+ T cells proliferate comparably 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 a conserved ability of TRM and circulating memory T cells to use infection-elicited γC-dependent cytokines for enhanced proliferation, likely to promote maintenance, and that treatment with γC-dependent cytokines can drive rapid proliferation without a need to identify antigens. N. N. J. Damon Runyon Cancer Research Foundation Fellow DRG-2427-21 K. M. W. NCI F30 H. B. d. S. CRI/Paul Shiverick Fellow; NIAID K99/R00 AI139381 S. C. J. NIAID R01 AI038903