Responsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8+ T cell subsets

Nicholas N. Jarjour, Kelsey M. Wanhainen, Changwei Peng, Noah V. Gavil, Nicholas J. Maurice, Henrique Borges da Silva, Ryan J. Martinez, Talia S. Dalzell, Matthew A. Huggins, David Masopust, Sara E. Hamilton, Stephen C. Jameson

Research output: Contribution to journalArticlepeer-review


Interleukin-15 (IL-15) is often considered a central regulator of memory CD8+ T cells, based primarily on studies of recirculating subsets. However, recent work identified IL-15–independent CD8+ T cell memory populations, including tissue-resident memory CD8+ T cells (TRM) in some nonlymphoid tissues (NLTs). Whether this reflects the existence of IL-15–insensitive memory CD8+ T cells is unclear. We report that IL-15 complexes (IL-15c) stimulate rapid proliferation and expansion of both tissue-resident and circulating memory CD8+ T cell subsets across lymphoid and nonlymphoid tissues with varying magnitude by tissue and memory subset, in some sites correlating with differing levels of the IL-2Rβ. This was conserved for memory CD8+ T cells recognizing distinct antigens and elicited by different pathogens. Following IL-15c–induced expansion, divided cells contracted to baseline numbers and only slowly returned to basal proliferation, suggesting a mechanism to transiently amplify memory populations. Through parabiosis, we showed that IL-15c drive local proliferation of TRM, with a degree of recruitment of circulating cells to some NLTs. Hence, irrespective of homeostatic IL-15 dependence, IL-15 sensitivity is a defining feature of memory CD8+ T cell populations, with therapeutic potential for expansion of TRM and other memory subsets in an antigen-agnostic and temporally controlled fashion.

Original languageEnglish (US)
Article numbere2209021119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
StatePublished - Oct 25 2022


  • CD8 T cell memory
  • cytokine
  • tissue-resident memory

ASJC Scopus subject areas

  • General


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