Collaboration among the common gamma chain cytokine family supports circulating and tissue-resident CD8+ T cell memory 2259059

Introduction We recently demonstrated resilience of circulating and tissue-resident memory (TRM) CD8+ T cells to loss of interleukin-7 (IL-7) signaling, revealing a compensatory relationship with its fellow common gamma chain (γC) cytokine IL-15. We found that across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8+ T cells. This confers resilience to altered availability of either cytokine, in contrast to the widely accepted model of exclusive roles for each in CD8+ T cell memory. How the broader γC cytokine family supports memory CD8+ T cells (especially TRM) in homeostasis and particularly inflammation is unclear. We hypothesize that conserved γC cytokine sensitivity confers adaptability extending beyond IL-7/15 when cytokine availability is altered. Methods We have now used cytokine therapies and infection to interrogate the broader capacity of pathogen-specific memory CD8+ T cells to adapt to cytokine availability, irrespective of homeostatic requirements. Results All γC cytokines assessed were capable of eliciting proliferation and expansion of circulating and tissue-resident memory CD8+ T cells, albeit with cytokine-, tissue-, and subset-specific nuance. This was a conserved feature of memory CD8+ T cells of different specificities and elicited by different pathogens, occurring in response to cytokines alone without cognate antigen. We observed similar behavior of bystander virus-specific memory CD8+ T cells during helminth infection. Conclusion Thus, irrespective of dependence, circulating and tissue-resident memory CD8+ T cells share cell-intrinsic sensitivity to multiple γC cytokines within tissue- and subset-specific constraints, providing additional adaptability. We propose that adaptability is a fundamental feature of CD8+ T cell memory, conferring resilience to changing tissue environments and inflammation to preserve immune memory. γC cytokine therapies are also an antigen-agnostic means to expand TRM in the laboratory and potentially the clinic. Funding Source NIAID: K22 AI177360 (NNJ), F31 AI176750 (SDO), F31 AI188630 (TAD), T32 AI007313 (KMA), K99/R00 AI139381 (HBdS), R01 AI038903 (SCJ). Damon Runyon Cancer Research Foundation DRG-2427-21 (NNJ). NCI: F30 CA250321 (KMW), K00 CA245735 (NJM), K99 CA296729 (NJM), F30 CA253992 (NVG).