Mucosal Associated Invariant T cells in the Obese-asthma endotype

ABSTRACT Asthma is an inflammatory lung disease that affects >300 million people worldwide. Although mild asthma is driven by a Th2-associated, eosinophil-dominated immune response, factors such as obesity/metabolic dysfunction are associated with more severe asthma. Thus, 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 obese asthma is due to deficiencies in common mouse models of obesity; standard high-fat diet (HFD)-fed mouse models are unable to induce extensive weight gain and metabolic dysfunction (associated with obesity in humans) in female mice - a major shortcoming given the female bias observed in the obese asthma endotype. Importantly, our group has determined 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 asthmatic mice demonstrate: (1) worse asthmatic outcomes compared to lean asthma controls, (2) a shift away from Th2 inflammation to a pro-inflammatory profile (Th17 or Th2/Th17), and (3) a pronounced female bias. Similar changes are NOT observed in male mice. These data suggest that TN housed obese female asthmatic mice model the human obese asthma endotype. Importantly, obese asthmatic female mice demonstrated a profound increase in the frequency of IL-17A-producing cells in the lungs, particularly mucosal-associated invariant T (MAIT) cells. MAIT cells are innate-like T cells abundant in lungs, liver, and adipose tissue. Although considered protective in models of lean asthma, in obesity, liver and adipose tissue MAIT switch to a pro-inflammatory state and contribute to metabolic dysfunction. In this application we hypothesize that, in obesity, liver and adipose tissue MAIT cells become pro-inflammatory and are licensed to migrate to the lung, where they drive severe asthma outcomes in female obese-asthmatic mice. This hypothesis will be tested in two Specific Aims. Aim 1: To define the functional and phenotypic differences of tissue resident MAIT cells in obese asthmatic females. We will examine patterns of MAIT cell accumulation and cytokine expression in lung and metabolic tissue (liver, white adipose tissue) over time, quantify differential MAIT cell responsiveness to TCR- dependent and independent signals, and perform non-biased transcriptional profiling of lung MAIT cells from lean and obese asthmatic female mice. Aim 2: To determine the role of MAIT cells in asthma outcomes in obese female mice. We will treat lean and obese asthmatic mice with a MAIT cell inhibitory ligand or adoptively transfer lung MAIT cells from lean or obese asthmatic mice and assess their necessity and sufficiency on the asthma phenotype. Completion of the proposed studies will facilitate a better understanding of the mechanisms underlying the unique clinical parameters associated with “obese asthma” and MAIT cell biology.