biostudies-literatureJarjour NNHHS | NIH | National Cancer InstituteNIAID NIH HHSHHS | NIH | National Institute of Allergy and Infectious DiseasesNCI NIH HHSDamon Runyon Cancer Research Foundatione2209021119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9618124biostudies-literatureUnknown119(43)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 memoryProceedings of the National Academy of Sciences of the United States of AmericaResponsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8⁺ T cell subsets.PMC9618124AI139381R29 AI038903R37 AI038903K99 AI139381AI038903F99 CA245735F30 CA250321CA245735DRG-2427-21K00 CA245735F30 CA253992CA250321R01 AI038903CA253992R00 AI139381Hamilton SEJarjour NNMaurice NJDalzell TSMartinez RJPeng CJameson SCBorges da Silva HHuggins MAGavil NVWanhainen KMMasopust DfalseResponsiveness 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 memory2022-01-01T00:00:00Z2022 Oct2026-03-31T11:52:58.165Z2025-04-04T22:59:06.688ZS-EPMC96181243626074510.1073/pnas.2209021119