Abstract

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-2/15Rβγc complex to initiate signaling. IL-15-deficient and IL-15Rα-deficient mice display similar alterations in immune cell subsets. Thus, the trimeric IL-15Rαβγc 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 via the IL-15Rβγc dimer. Here, we compared the ability of mice lacking IL-15 (no signaling) or IL-15Rα (partial/distinct signaling) to control Listeria monocytogenes 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 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 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 via the IL-15Rβγc dimeric complex is necessary and sufficient for the induction of IFNγ from sources other than NK/NKT cells to control bacterial pathogens.

Highlights

  • Interleukin-15 (IL-15) is a multi-faceted cytokine that facilitates the activation of myeloid and lymphoid components of the innate immune response to pathogens [1,2,3]

  • The bacterial load observed in Il15-/- male mice was comparable to that of Ifng-/- male mice, indicating that IL-15 is as important as IFNg in controlling L. monocytogenes infection (Figure 1B)

  • The dispensability of IL-15Ra but not IL-15 to clear low dose L. monocytogenes infection indicated that IL-15 signaling can occur independently of IL-15Ra and that this signaling plays a key role in the control of bacterial infections

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Summary

Introduction

Interleukin-15 (IL-15) is a multi-faceted cytokine that facilitates the activation of myeloid and lymphoid components of the innate immune response to pathogens [1,2,3]. IL-15 is expressed by activated macrophages and dendritic cells (DC) as well as stromal cells in the bone marrow and thymus and intestinal epithelial cells [4]. Transgenic expression of human IL-15 increases NK and memory CD8+ T cells but not monocytes or B cells [2, 8, 9]. Mechanistic studies revealed that the biological activities of IL-15 on lymphoid cells are mediated by IL-15 bound to IL-15Ra during biosynthesis and ‘trans-presentation’ of the IL-15:IL-15Ra (IL15:15Ra) complex to responder cells expressing the IL-2/15Rbgc heterodimeric receptor complex, explaining the similarity in the phenotype of Il15-/- and Il15ra-/- mice [6, 7, 10]

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