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

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 (T_RM) 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 T_RM, 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 T_RM and other memory subsets in an antigen-agnostic and temporally controlled fashion.