This proposal seeks to understand the processes driving the increasing prevalence of allergic immune diseases in developing countries. This type of immunity, here termed type 2 immunity, commonly occurs during intestinal helminth infection, and likely underlies the evolution of this host response. We and others have noted the association of cellular constituents of allergic immunity, including eosinophils and alternatively activated macrophages, in mouse visceral adipose tissues, where these cells are required to sustain normal metabolic homeostasis. As shown here, these cell types are maintained in adipose tissues by constitutive activation of innate helper type 2 (ILC2) cells, a novel type of innate lymphoid cell simultaneously reported by this and two other laboratories. This grant seeks to answer the hypothesis that ILC2 cells link mucosal integrity with metabolic homeostasis by attenuating lung and intestinal mucosal inflammation while sustaining systemic energy demands. The grant seeks to pursue this hypothesis in 3 Specific Aims: 1. To establish the role of ILC2 cells in immune and metabolic homeostasis associated with allergic inflammatory challenge;2. To establish the role of ILC2 cells in immune and metabolic homeostasis in animals with genetic deficiencies associated with mucosal inflammation of the lung and intestinal mucosa;and 3. To assess the effects of intestinal parasitic infection on the microbiome and the role of type 2 cytokines in mediating these effects. The novel technical approach involves the use of unique lines of mice established in my laboratory with knockin fluorescent markers containing embedded Cre elements that facilitate cell function-marking, fate-mapping and cell-specific deletion based on function with a high degree of precision. Our approach will open up new lines of investigation in understanding the evolutionary role of ILC2 cells and possibly yield insights into the relationship of allergic immunity, mucosal integrity and systemic energy homeostasis.

Public Health Relevance

Allergic immunity is an increasing problem in developed countries, including the United States, but little is known regarding the basic mechanisms driving this process. This grant proposes that a new type of innate lymphoid cell may link inflammation of the linings of the lung and intestines with how energy is utilized, and thus contribute to our understanding of factors that might be driving epidemics of allergy, inflammation and obesity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Nusse, Ysbrand M; Savage, Adam K; Marangoni, Pauline et al. (2018) Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559:109-113
Ricardo-Gonzalez, Roberto R; Van Dyken, Steven J; Schneider, Christoph et al. (2018) Tissue signals imprint ILC2 identity with anticipatory function. Nat Immunol 19:1093-1099
Schneider, Christoph; O'Leary, Claire E; von Moltke, Jakob et al. (2018) A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling. Cell 174:271-284.e14
Van Dyken, Steven J; Liang, Hong-Erh; Naikawadi, Ram P et al. (2017) Spontaneous Chitin Accumulation in Airways and Age-Related Fibrotic Lung Disease. Cell 169:497-509.e13
Savage, Adam K; Liang, Hong-Erh; Locksley, Richard M (2017) The Development of Steady-State Activation Hubs between Adult LTi ILC3s and Primed Macrophages in Small Intestine. J Immunol 199:1912-1922
von Moltke, Jakob; O'Leary, Claire E; Barrett, Nora A et al. (2017) Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s. J Exp Med 214:27-37
Mohapatra, A; Van Dyken, S J; Schneider, C et al. (2016) Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal Immunol 9:275-86
Van Dyken, Steven J; Nussbaum, Jesse C; Lee, Jinwoo et al. (2016) A tissue checkpoint regulates type 2 immunity. Nat Immunol 17:1381-1387
von Moltke, Jakob; Ji, Ming; Liang, Hong-Erh et al. (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529:221-5
Lee, Min-Woo; Odegaard, Justin I; Mukundan, Lata et al. (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74-87

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