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

Introduction/Rationale: 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.