AUTHOR=Nandi Madhuparna , Moyo Mitterrand Muamba , Orkhis Sakina , Mobulakani Jeanne Masunga Faida , Limoges Marc-André , Rexhepi  Fjolla , Mayhue Marian , Cayarga Anny Armas , Marrero Gisela Cofino , Ilangumaran Subburaj , Menendez Alfredo , Ramanathan Sheela 

TITLE=IL-15Rα-Independent IL-15 Signaling in Non-NK Cell-Derived IFNγ Driven Control of Listeria monocytogenes

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.793918

DOI=10.3389/fimmu.2021.793918

ISSN=1664-3224

ABSTRACT=<p>Interleukin-15, produced by hematopoietic and parenchymal cells, maintains immune cell homeostasis and facilitates activation of lymphoid and myeloid cell subsets. IL-15 interacts with the ligand-binding receptor chain IL-15Rα during biosynthesis, and the IL-15:IL-15Rα complex is trans-presented to responder cells that express the IL-2/15Rβγ<sub>c</sub> complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαβγ<sub>c</sub> complex is considered the functional IL-15 receptor. However, studies on the pathogenic role of IL-15 in inflammatory and autoimmune diseases indicate that IL-15 can signal independently of IL-15Rα <italic>via</italic> the IL-15Rβγ<sub>c</sub> dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control <italic>Listeria monocytogenes</italic> infection. We show that IL-15-deficient mice succumb to infection whereas IL-15Rα-deficient mice clear the pathogen as efficiently as wildtype mice. IL-15-deficient macrophages did not show any defect in bacterial uptake or iNOS expression <italic>in vitro</italic>. <italic>In vivo</italic>, IL-15 deficiency impaired the accumulation of inflammatory monocytes in infected spleens without affecting chemokine and pro-inflammatory cytokine production. The inability of IL-15-deficient mice to clear <italic>L. monocytogenes</italic> results from impaired early IFNγ production, which was not affected in IL-15Rα-deficient mice. Administration of IFNγ partially enabled IL-15-deficient mice to control the infection. Bone marrow chimeras revealed that IL-15 needed for early bacterial control can originate from both hematopoietic and non-hematopoietic cells. Overall, our findings indicate that IL-15-dependent IL-15Rα-independent signaling <italic>via</italic> the IL-15Rβγ<sub>c</sub> dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.</p>