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

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.

Interleukin 15 in murine models of colitis

“…Studies using Il15 −/− mice have implicated IL‐15 in immune responses against oral Salmonella infection by promoting the activity of IL‐15‐dependent NK cells (Ashkar et al, 2009). However, we have shown that while Il15 −/− mice are highly susceptible to systemic low‐dose Listeria monocytogenes infection, Il15ra −/− mice are not (Nandi et al, 2021), even though NK cells and ILC1s require both IL‐15 and IL‐15Rα for their maintenance and activation (Fuchs et al, 2013; Lodolce et al, 1998; Schluns et al, 2004). To determine whether this difference is maintained for Salmonella infections (and hence, establish base‐line Il15 −/− and Il15ra −/− mice susceptibility to Salmonella ), we infected mice orally with 5 × 10 7 cfu of the virulent Salmonella SL1344 strain.…”

“…C. rodentium colonizes the intestinal lumen without causing invasive infection. As mice without IL‐15 were more susceptible to Listeria monocytogenes (Nandi et al, 2021) and non‐virulent Salmonella (Figure 1c), as opposed to mice without IL‐15Rα, we assessed the kinetics of C. rodentium fecal load after oral infection in WT, Il15 −/− , mice and Il15ra −/− mice. On Day 14 post‐infection, irrespective of the genotype, the bacterial load was comparable (Figure S4A).…”

“…C. rodentium colonizes the intestinal lumen without causing invasive infection. As mice without IL-15 were more susceptible to Listeria monocytogenes (Nandi et al, 2021) and non-virulent Salmonella (Figure 1c), as opposed to mice without IL-15Rα, we assessed the F I G U R E 3 Histological analyses of colon and cecum at 24 hpi in Salmonella-induced colitis. (a) H&E staining of one representative section of cecum and colon from mice from each genotype at 24 hpi.…”

“…Interpretation of the role of IL-15 in infectious colitis is complicated by the requirement for IL-15 but not IL-15Rα during early innate immune responses (Nandi et al, 2021). Yoshihara et al (2006) have previously shown that Il15 À/À mice were resistant to DSS-induced colitis.…”

“…Il15 À/À mice do not form granulomas during Propionibacterium acnes infection, suggesting a key role for IL-15 in the early activation of innate immune responses (Ohteki et al, 2006). Il15 À/À mice are highly sensitive to various viral, fungal, and bacterial infections (Ashkar et al, 2009;Bobbala et al, 2017;Dominguez-Andres et al, 2017;Mitani et al, 1999;Nishimura et al, 2001;Soudja et al, 2012;Takano et al, 1998). IL-15 is implicated in chronic inflammation and is a pathogenic factor in tissuespecific autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease (IBD), autoimmune diabetes, and psoriasis (Allard-Chamard et al, 2020;Bobbala et al, 2012;Bobbala et al, 2017;Di Sabatino et al, 2006;McInnes et al, 1997;Meresse et al, 2004;Waldmann, 2004;Waldmann, 2006;Waldmann et al, 2020).…”