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Tracking the Foundations of Allergic Immunity

Research Summary

Richard Locksley’s laboratory investigates the orchestration of innate and adaptive immunity in vivo using mice with engineered marker alleles that facilitate tracking rare cells and their functions.  His laboratory contributed to the discovery of group 2 innate lymphoid cells, or ILC2s, which have been implicated not only in allergic diseases, such as asthma, but also increasingly in processes linked to normal tissue homeostasis.

The immune system arose to protect us from infectious agents. This is most easily seen by the efficacy of vaccines, which induce antibodies that bind to and neutralize pathogenic viruses and bacteria before they can replicate and cause tissue damage. Much has been learned about the pathways necessary for the induction of successful immunity. Minimally, this includes the recognition of conserved constituents, such as bacterial cell wall moieties and bacterial and viral nucleic acids, which announce the invader as "foreign," together with the molecular details specific to each pathogen, which are recognized by the highly discriminatory antigen receptors of the adaptive immune cells, T cells and B cells. The communication between innate cells and adaptive cells is mediated by an array of cytokines that comprise the language of the immune system. Following these highly controlled cytokine communications provides a mechanism for probing how the immune system works and for determining what happens when things become dysregulated and cause pathology.   

Vertebrate immunity is organized into modules such that stereotyped patterns of cytokines—the immune "language"—are used during responses to different types of organisms. For rapidly replicating pathogens, like most bacteria, viruses, and fungi, inflammatory cytokines mediate the recruitment and activation of cells to enhanced microbicidal states (represented by activated macrophages, for instance) that are necessary to kill organisms and limit infection. Although these inflammatory responses can lead to pathology, such as seen in septic shock, regulatory processes are also invoked that control the immune attack and re-establish homeostasis through mechanisms that additionally lead to the establishment of protective memory T cells and antibody-producing B cells and plasma cells. The evolutionary importance of these immune responses is underscored by the consequences of human mutations in these pathways that lead to an inability to contain infectious organisms.

While these protective responses are fairly well understood, the immune response typified as "allergy" remains more puzzling.  Allergic inflammation is characterized by the infiltration of tissues by eosinophils and basophils, which are rare myeloid cells that comprise only a few percent of circulating blood cells. The adaptive allergic response is characterized by increases in the numbers of Th2 cells that release interleukin-4 (IL-4), IL-5, and IL-13 and the development of plasma cells that secrete immunoglobulin E (IgE). When sustained, these responses can lead to alterations at mucosal epithelial surfaces, including increases in the number of mucus-secreting cells and increased deposition of collagen in the tissues. These responses can be protective in healing the epithelium from chronic attack by parasitic worms, such as hookworms and schistosomes. However, when this type of immunity becomes focused on common environmental exposures, such as inhaled dust mites or mold or consumed shellfish, the result can be allergies, including potentially life-threatening afflictions such as asthma and food allergy, which affect, respectively, more than 20 million and 2 million Americans.

Group 2 innate lymphoid cells (ILC2) in mouse lung

Our laboratory defined an environmental trigger, chitin, which is a polysaccharide required for structural integrity in insects, fungi, and helminthes, as a potent stimulus for activation of innate cytokines associated with allergic, or type 2, immunity.  Further investigation revealed that the target of chitin was rare innate lymphoid cells, now termed group 2 innate lymphoid cells, or ILC2s, that constitute the major innate source of IL-13 and IL-5, key cytokines that comprise the "language" of allergy. These ILC2s are dispersed throughout tissues during fetal development and, when activated, result in a stereotyped cytokine response that mediates the accumulation of eosinophils and "alternatively activated" macrophages in affected tissues. With continued stimulation, adaptive responses characterized by recruitment of Th2 cells and production of IgE occurs, thus exposing a fundamental pathway central to allergic immunity.

One of our major focuses remains the endogenous upstream signals that activate ILC2s and the downstream signals by which the tissues respond to re-establish homeostasis. When administered to animals, chitin induces focal areas of mucosal injury, leading to the production of epithelial cytokines TSLP, IL-33, and IL-25. ILC2s constitutively express receptors for these cytokines, and respond by secreting cytokines and growth factors. In the absence of these three epithelial cytokines, ILC2 cytokines are not released, and, when ILC2s are deleted, the infiltration of inflammatory cells and the extent of tissue injury are increased.  A major target of IL-13 derived from activated ILC2s is induction of epithelial mucins and chitinase enzymes that clear and degrade the insoluble polysaccharide, thus re-establishing airway homeostasis. A major target of IL-5 is the accumulation of tissue eosinophils, although their precise role remains undefined. We continue efforts to understand the role of these epithelial processes in maintaining lung homeostasis against environmental challenges and have begun to extend these findings to human lung diseases characterized by inflammation, tissue injury, and subepithelial fibrosis, such as asthma, to understand how they become dysregulated.

Despite elevated Th2 cells, eosinophils and IgE, human intestinal helminth infections are not cleared over many years, suggesting that helminthes may exploit these pathways for their own survival. In an effort to define physiologic roles for eosinophils, we noted that these rare cells reside constitutively in visceral adipose tissue and small intestine lamina propria. We confirmed that alternatively activated macrophages were also localized to these sites, suggesting that local ILC2 activation might explain the residence of these innate cells otherwise associated with allergy. We showed that eosinophils were necessary to sustain normal cellular homeostasis in adipose tissues and that eosinophil-deficient mice were unable to control metabolic responses when placed on high-fat diet. Unexpectedly, the presence of eosinophils was due to ILC2s in adipose tissue, where these cells constitutively secreted cytokines required for eosinophil recruitment and for the alternative activation of macrophages. Indeed, using novel mice with activation-induced deletion of ILC2s, we demonstrated that serum IL-5 necessary for basal bone marrow eosinophilopoiesis is derived from tissue ILC2s, and that ILC2s constitutively express receptors for intestinal neuropeptides that activate these cells in response to food intake. These studies have uncovered basal physiologic conditions regulated by these rare "allergic" cells, and have opened new avenues of investigation into potential roles for these cells in vertebrate biology in metabolism, wound healing and adaptive thermogenesis. 

Grants from the National Institutes of Health provided partial support for this project.

As of July 23, 2014

Scientist Profile

Investigator
University of California, San Francisco
Immunology, Medicine and Translational Research