Asthma is an inflammatory lung disease that affects >300 million people worldwide. Obesity/metabolic
dysfunction, which affect 40% of adults in the US, is associated with a more severe asthma endotype. Unlike
mild asthma which is driven by a Th2 immune response, the “obese asthma” endotype is associated with frequent
asthma exacerbations, a shift away from Th2-dominated inflammation towards a Th17-dominated profile, and a
marked female bias. A major gap in our understanding of mechanisms driving the “obese asthma” endotype is
due to deficiencies in common mouse models of obesity. Standard mouse models of high-fat diet (HFD) driven
obesity are unable to induce extensive weight gain and metabolic dysfunction in female mice - a major
shortcoming given the female bias of the “obese asthma“ endotype. Our group has uncovered that HFD feeding
of C57BL/6 mice housed at a temperature in which they are at metabolic homeostasis (thermoneutral
temperature (TN); 30-33°C) promotes severe obesity and metabolic dysfunction in female mice. Preliminary data
using this model demonstrate that allergen-challenged obese female mice exhibit: (1) worse asthma outcomes
compared to lean controls; (2) reduced markers of type 2 immunity (eosinophilia, Th2 cytokine production); and
(3) a selective increase in the IL-17A production by innate lymphocytes, particularly gd T cells and Mucosal
Associated Invariant T cells (MAIT cells). Critically, none of these changes are observed in obese asthmatic
male mice. Although both gd T cells and MAIT cells have been ascribed protective roles in the context of asthma
and metabolic homeostasis, in obesity their proinflammatory vigor increases, and they become important
mediators of glucose intolerance, insulin resistance, and tissue inflammation invoking extreme functional
plasticity. Importantly, no studies have examined the role of these cells in obese asthma to date. Based on our
novel preliminary data, we hypothesize that, innate lymphoid populations (gd T cells, MAIT cells) acquire
pathogenic functions in obese female mice and contribute to the development of the “obese asthma”
endotype. This hypothesis will be tested in two aims. Aim 1: To determine if gd T cells or MAIT are necessary
and sufficient to trigger more severe asthma in obese female mice. Using gd T cell or MAIT cell blocking
agents, and adoptive transfer of purified gd T cell/MAIT populations from lean or obese asthmatic females to lean
asthmatic male and female mice, followed by assessment of asthma and metabolic endpoints, we will determine
the necessity and sufficiency of these cells in obese asthma. Aim 2: To compare the proinflammatory and
metabolic landscapes of innate lymphocytes from lean and obese asthmatic female mice. Transcriptional
landscape of purified lung innate lymphocyte populations (gd T cells, MAIT cells, ILCs, iNKT T cells) from lean
and obese asthmatic female mice will be analyzed. Changes in inflammatory and metabolic pathway gene
expression will be correlated to asthma and obesity-related sequelae severity. Notably, completion of these
studies will advance understanding of the mechanisms underlying “obese asthma” endotype.