TY - JOUR
T1 - Responsiveness to interleukin-15 therapy is shared between tissue-resident and circulating memory CD8+ T cell subsets
AU - Jarjour, Nicholas N.
AU - Wanhainen, Kelsey M.
AU - Peng, Changwei
AU - Gavil, Noah V.
AU - Maurice, Nicholas J.
AU - da Silva, Henrique Borges
AU - Martinez, Ryan J.
AU - Dalzell, Talia S.
AU - Huggins, Matthew A.
AU - Masopust, David
AU - Hamilton, Sara E.
AU - Jameson, Stephen C.
N1 - Publisher Copyright:
© 2022 the Author(s). Published by PNAS.
PY - 2022/10/25
Y1 - 2022/10/25
N2 - 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.
AB - 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.
KW - CD8 T cell memory
KW - cytokine
KW - tissue-resident memory
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U2 - 10.1073/pnas.2209021119
DO - 10.1073/pnas.2209021119
M3 - Article
C2 - 36260745
AN - SCOPUS:85140415634
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
M1 - e2209021119
ER -