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)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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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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Bando, Jennifer K; Liang, Hong-Erh; Locksley, Richard M (2015) Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat Immunol 16:153-60
von Moltke, Jakob; Locksley, Richard M (2014) I-L-C-2 it: type 2 immunity and group 2 innate lymphoid cells in homeostasis. Curr Opin Immunol 31:58-65
Patnode, Michael L; Bando, Jennifer K; Krummel, Matthew F et al. (2014) Leukotriene B4 amplifies eosinophil accumulation in response to nematodes. J Exp Med 211:1281-8
Van Dyken, Steven J; Mohapatra, Alexander; Nussbaum, Jesse C et al. (2014) Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and ?? T cells. Immunity 40:414-24
Nussbaum, Jesse C; Van Dyken, Steven J; von Moltke, Jakob et al. (2013) Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245-8
Van Dyken, Steven J; Locksley, Richard M (2013) Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu Rev Immunol 31:317-43
Bando, Jennifer K; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung. J Leukoc Biol 94:877-84
Cheng, Laurence E; Hartmann, Karin; Roers, Axel et al. (2013) Perivascular mast cells dynamically probe cutaneous blood vessels to capture immunoglobulin E. Immunity 38:166-75
Molofsky, Ari B; Nussbaum, Jesse C; Liang, Hong-Erh et al. (2013) Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med 210:535-49
Liang, Hong-Erh; Reinhardt, R Lee; Bando, Jennifer K et al. (2012) Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity. Nat Immunol 13:58-66

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