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

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-15R alpha during biosynthesis, and the IL-15:IL-15R alpha complex is trans-presented to responder cells that express the IL-2/15R beta gamma(c) complex to initiate signaling. IL-15-deficient and IL-15R alpha-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15R alpha beta gamma(c) 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-15R alpha via the IL-15R beta gamma(c) dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15R alpha (partial/distinct signaling) to control Listeria monocytogenes infection. We show that IL-15-deficient mice succumb to infection whereas IL-15R alpha-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 in vitro. In vivo, 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 L. monocytogenes results from impaired early IFN gamma production, which was not affected in IL-15R alpha-deficient mice. Administration of IFN gamma 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-15R alpha-independent signaling via the IL-15R beta gamma(c) dimeric complex is necessary and sufficient for the induction of IFN gamma from sources other than NK/NKT cells to control bacterial pathogens.

Automated summary

Interleukin-15 (IL-15) regulates immune cell activity by forming a trimeric complex with IL-15Rα, but can also signal through the IL-15Rβγ(c) dimer. IL-15 deficiency results in the inability to control bacterial infections, while mice lacking IL-15Rα are able to effectively clear pathogens.