IL-22 mediates host defense against an intestinal intracellular parasite in the absence of IFN-γ at the cost of Th17-driven immunopathology.
ABSTRACT The roles of Th1 and Th17 responses as mediators of host protection and pathology in the intestine are the subjects of intense research. In this study, we investigated a model of intestinal inflammation driven by the intracellular apicomplexan parasite Eimeria falciformis. Although IFN-γ was the predominant cytokine during E. falciformis infection in wild-type mice, it was found to be dispensable for host defense and the development of intestinal inflammation. E. falciformis-infected IFN-γR(-/-) and IFN-γ(-/-) mice developed dramatically exacerbated body weight loss and intestinal pathology, but they surprisingly harbored fewer parasites. This was associated with a striking increase in parasite-specific IL-17A and IL-22 production in the mesenteric lymph nodes and intestine. CD4(+) T cells were found to be the source of IL-17A and IL-22, which drove the recruitment of neutrophils and increased tissue expression of anti-microbial peptides (RegIIIβ, RegIIIγ) and matrix metalloproteinase 9. Concurrent neutralization of IL-17A and IL-22 in E. falciformis-infected IFN-γR(-/-) mice resulted in a reduction in infection-induced body weight loss and inflammation and significantly increased parasite shedding. In contrast, neutralization of IL-22 alone was sufficient to increase parasite burden, but it had no effect on body weight loss. Treatment of an E. falciformis-infected intestinal epithelial cell line with IFN-γ, IL-17A, or IL-22 significantly reduced parasite development in vitro. Taken together, to our knowledge these data demonstrate for the first time an antiparasite effect of IL-22 during an intestinal infection, and they suggest that IL-17A and IL-22 have redundant roles in driving intestinal pathology in the absence of IFN-γ signaling.
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ABSTRACT: Unlike adaptive immune cells that require antigen recognition and functional maturation during infection, innate lymphoid cells (ILCs) usually respond to pathogens promptly and serve as the first line of defense in infectious diseases. RAR-related orphan receptor (RORγt)(+) group 3 ILCs are one of the innate cell populations that have recently been intensively studied. During the fetal stage of development, RORγt(+) group 3 ILCs (e.g., lymphoid tissue inducer cells) are required for lymphoid organogenesis. In adult mice, RORγt(+) group 3 ILCs are abundantly present in the gut to exert immune defensive functions. Under certain circumstances, however, RORγt(+) group 3 ILCs can be pathogenic and contribute to intestinal inflammation. Aryl hydrocarbon receptor (Ahr), a ligand-dependent transcriptional factor, is widely expressed by various immune and non-immune cells. In the gut, the ligand for Ahr can be derived/generated from diet, microflora, and/or host cells. Ahr has been shown to regulate different cell populations in the immune system including RORγt(+) group 3 ILCs, T helper (Th)17/22 cells, γδT cells, regulatory T cells (Tregs), Tr1 cells, and antigen presenting cells. In this review, we will focus on the development and function of RORγt(+) group 3 ILCs, and discuss the role of Ahr in intestinal immunity and inflammation in mice and in humans. A better understanding of the function of Ahr in the gut is important for developing new therapeutic means to target Ahr in future treatment of infectious and autoimmune diseases.Seminars in Immunopathology 08/2013; · 5.38 Impact Factor
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ABSTRACT: Interleukin (IL)-22 has redundant, protective or pathogenic functions during auto-immune, inflammatory and infectious diseases. Here, we addressed the potential role of IL-22 in host defence and pathogenesis during lethal and sublethal respiratory H3N2 influenza A virus (IAV) infection. We show that IL-22, as well as factors associated with its production, are expressed in the lung tissue during the early phases of IAV infection. Our data indicate that RORγt-positive αβ and γδ T cells, as well as innate lymphoid cells, expressed enhanced Il22 transcripts as early as two days post-infection. During lethal or sublethal IAV infections, endogenous IL-22 played no role in the control of IAV replication and in the development of the IAV-specific CD8(+) T cell response. During lethal infection, where wild-type (WT) mice succumbed to severe pneumonia, the lack of IL-22 did not accelerate or delay IAV-associated pathogenesis and animal death. In stark contrast, during sublethal IAV infection, IL-22 deficient animals had an enhanced lung injury and showed a lower airway epithelial integrity relative to WT littermates. Of importance, the protective effect of endogenous IL-22 in pulmonary damages was associated with a more controlled secondary bacterial infection. Indeed, after challenge with Streptococcus pneumoniae, IAV-experienced Il22(-/-) animals were more susceptible than WT controls in terms of survival rate and bacterial burden in the lungs. Together, IL-22 plays no major role during lethal influenza but is beneficial during sublethal H3N2 IAV infection where it limits lung inflammation and subsequent bacterial superinfections.Journal of Virology 04/2013; · 5.08 Impact Factor
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ABSTRACT: The molecular and cellular mechanisms leading to immune protection against Eimeria avian coccidiosis are complex and include multiple aspects of innate and adaptive immunities. Innate immunity is mediated by various subpopulations of immune cells that recognize pathogen associated molecular patterns (PAMPs) through their pattern recognition receptors (PRRs) leading to the secretion of soluble factors with diverse functions. Adaptive immunity, which is important in conferring protection against subsequent reinfections, involves subtypes of T and B lymphocytes that mediate antigen-specific immune responses. Recently, global gene expression microarray analysis has been used in an attempt to dissect this complex network of immune cells and molecules during avian coccidiosis. These new studies emphasized the uniqueness of the innate immune response to Eimeria infection, and directly led to the discovery of previously uncharacterized host genes and proteins whose expression levels were modulated following parasite infection. Among these is the IL-17 family of cytokines. This review highlights recent progress in IL-17 research in the context of host immunity to avian coccidiosis.Developmental and comparative immunology 04/2013; · 3.29 Impact Factor