Research

The Locksley lab investigates the cellular and molecular underpinnings of allergic immunity. Our strategy involves the use of function-tracking mice whose cells report the expression of cytokines and enzymes implicated in the elaboration of this type of inflammation. Major projects in the laboratory involve understanding the interactions between innate and adaptive immune cells during allergic inflammation and using these insights to guide our understanding of roles for these cells in homeostatic processes related to normal tissue physiology. Such studies have already uncovered unexpected roles for these cells in metabolism and tissue integrity. Our overall aim is to understand the evolutionary pressures that underpin the primary roles for the various populations of innate cells that, when dysregulated, manifest as allergic and atopic diseases that have become major afflictions of humans.

ILC2 biology and the roots of allergic immunity

Tuft cells link environmental signals to ILC2 activation

Chitin turnover and airway homeostasis

ILC2 biology and the roots of allergic immunity

ILC2s are tissue-resident cells that position in diverse organs around the time of birth. Different signals activate resident ILC2s in different tissues to secrete canonical cytokines and growth factors, and these outputs impact local tissue function. Using lineage-tracking and activation markers, we are trying to understand the ontogeny of ILC2s in different organs, their turn-over, and tissue-specific signals and their effects on ILC2 expansion, life-span and epigenetic alterations. Under conditions of allergic inflammation, Th2 cells can become tissue-resident and long-lived. We are investigating the relationships among organ-specific ILC2s and Th2s in attempting to de-code the tissue signals that serve to coordinate these inter-connections between resident innate and adaptive lymphoid lineages. Our goal is to define a tissue ‘map’ of regulatory elements that serve to activate allergic immunity in different body tissues, thus allowing more precise targeting of inflammation based on the tissues involved.

Tuft cells link environmental signals to ILC2 activation

We are attempting to understand how type 2 cytokines from ILC2s regulate tissue homeostasis in diverse organs where mechanistic pathways may differ but underlying principles may uncover shared biology. In small intestine, lamina propria ILC2s express high levels of IL-25 receptor. Using reporter mice, we discovered that tuft cells, rare mucosal epithelial cells in all vertebrates, are the major source of IL-25 (1). Intestinal perturbations, including by protists and helminths, activate tuft cells to elicit IL-13 production by lamina propria ILC2s. In turn, IL-13 acts on intestinal crypt progenitors to bias differentiation of epithelial cells to tuft and goblet cells, thus establishing a feed-forward circuit that alters small intestinal physiology. Protist symbionts like Tritrichomonas degrade fibrous polysaccharides and export short chain fatty acids, hydrogen and succinate as metabolites from the mitochrondria-like hydrogenosome; activation of the succinate receptor on small intestinal tuft cells activates the tuft cell – ILC2 circuit, which over time induces small intestinal remodeling characterized by lengthening and muscle hypertrophy (2). Such changes are important in establishing concomitant immunity, the process by which adult helminths induce a state of refractoriness to further colonization by new larvae of homologous and heterologous species. As shown in a separate investigation (3), the ability of parasitic helminths to initiate fetal-like stem cell reversion during development in the small intestinal niche emphasizes the evolutionary détente between these widespread colonizers and their vertebrate hosts.

Chitin turnover and airway homeostasis

Chitin is a widely prevalent biopolymer associated with the cells walls of fungi, insects and crustacea, as well as the pharynx and eggs of helminthes. These organisms and their products are frequently associated with allergic inflammation. Chitin, when administered to the airways of mice, induces a mixed influx of eosinophils and neutrophils due to activation of innate lung ILC2s and γδ T cells. Clearance of the insoluble polymer is mediated in part by a secreted chitinase, AMCase, one of two active chitinases expressed in mice and humans. Upon deletion of epithelial AMCase, which is expressed in specialized epithelia of the airways and stomach, mice begin to develop spontaneous airways inflammation characterized by activation of ILC2s and γδ T cells, which progresses over months to lung fibrosis and early mortality. Disease can be rescued by transgenic restoration of airway chitinase or by administration of recombinant chitinase to the lung. AMCase-deficient mice accumulate undigested chitin fibers in airways derived from environmental chitin in bedding and food. Patients with idiopathic pulmonary fibrosis also accumulate undigested chitin polymers in airway lavage, suggesting that damage to lung epithelia that diminishes AMCase secretion may lead to secondary inflammatory provocation due to the inability to clear environmentally-acquired chitin from airways. Studies are on-going to understand the characteristics of specialized epithelia expressing AMCase and the role of the enzyme in intestinal response to chitin in diet constituents.

Locksley Lab

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ILC2 biology and the roots of allergic immunity

Tuft cells link environmental signals to ILC2 activation

Chitin turnover and airway homeostasis