Soil transmitted helminths remain the most prevalent of all chronic human infections, with an estimated two billion people infected worldwide. Field and experimental studies indicate that immunity in infected individuals is associated with expression of T helper type 2 (Th2) cytokines, while persistent heavy infections can result in overproduction of proinflammatory cytokines and the development of severe intestinal inflammation. The goal of this proposal is to identify the innate immunologic events that occur following infection and interrogate how these responses influence T helper cell differentiation and subsequent resistance or susceptibility to infection. Employing an experimental model of Trichuris infection, our preliminary studies identified a critical role for intestinal epithelial cells (IECs) in the innate response to infection. Manipulation of IEC functions revealed that IECs can regulates multiple aspects of the anti-parasite immune response. First, expression of MHC class II in IECs appears to be critical for the development of Th2 cytokine-dependent immunity. Second, secretion of the cytokine thymic stromal lymphopoietin (TSLP) by IECs appears to be an important early event in influencing dendritic cell and CD4+ T cell responses required for worm expulsion and prevention of intestinal inflammation. Third, TSLP-TSLPR interactions appear to play a critical role in immunity to secondary Trichuris infection, suggesting IEC-derived cytokines may have an important influence on the function of Th2 memory cells. Employing cell lineage- specific deletions in MHC class II, TSLP or TSLPR, three specific aims of this project will determine (i) how IEC-intrinsic MHC class II expression governs the development and regulation Th2 cytokine responses, (ii) how TSLP-TSLPR interactions play a dual role in the development of Th2 cytokine responses and prevention of intestinal inflammation, and (iii) how IEC-derived TSLP regulates the maintenance and function of Trichuris-responsive Th2 memory cells. The results of these studies will provide a framework to test the therapeutic potential of manipulating IEC responses in the promotion of anti- helminth Th2 responses and treatment of infection-induced intestinal inflammation following gastrointestinal nematode infection. In addition, it is hoped that the findings of these studies will have broader implications for understanding the pathophysiology and treatment of multiple inflammatory diseases associated with dysregulated cytokine production including asthma, allergy and inflammatory bowel disease.
An estimated two billion people worldwide are infected with soil transmitted helminth parasites. Although there is strong evidence that T helper type 2 (Th2) cytokines are critical for immunity to infection, the early innate immune responses that promote protective Th2 cytokine responses are poorly defined. The goals of this proposal are to understand the role of intestinal epithelial cells in the development of protective immune responses and apply this knowledge in the design of successful new anti-helminth vaccines.
| Moriyama, Saya; Brestoff, Jonathan R; Flamar, Anne-Laure et al. (2018) ?2-adrenergic receptor-mediated negative regulation of group 2 innate lymphoid cell responses. Science 359:1056-1061 |
| Veiga-Fernandes, Henrique; Artis, David (2018) Neuronal-immune system cross-talk in homeostasis. Science 359:1465-1466 |
| Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20 |
| Chu, Coco; Moriyama, Saya; Li, Zhi et al. (2018) Anti-microbial Functions of Group 3 Innate Lymphoid Cells in Gut-Associated Lymphoid Tissues Are Regulated by G-Protein-Coupled Receptor 183. Cell Rep 23:3750-3758 |
| Klose, Christoph S N; Mahlakõiv, Tanel; Moeller, Jesper B et al. (2017) The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation. Nature 549:282-286 |
| Blander, J Magarian; Longman, Randy S; Iliev, Iliyan D et al. (2017) Regulation of inflammation by microbiota interactions with the host. Nat Immunol 18:851-860 |
| Wallrapp, Antonia; Riesenfeld, Samantha J; Burkett, Patrick R et al. (2017) The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation. Nature 549:351-356 |
| Monticelli, Laurel A; Buck, Michael D; Flamar, Anne-Laure et al. (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17:656-65 |
| Alex, Aneesh; Tait Wojno, Elia D; Artis, David et al. (2016) Label-Free Imaging of Eosinophilic Esophagitis Mouse Models Using Optical Coherence Tomography. Methods Mol Biol 1422:127-36 |
| Rak, Gregory D; Osborne, Lisa C; Siracusa, Mark C et al. (2016) IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing. J Invest Dermatol 136:487-496 |
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