Project Summary/Abstract Asthma remains a serious public health threat with unmet therapeutic needs. The development of successful therapies relies a more in-depth understanding of the immune subsets and pathways involved. MAIT cells are innate-like T cells that recognize microbial riboflavin metabolites presented by MR1 and can function through both TCR dependent and independent pathways. Interestingly, previous studies indicated an inverse association between MAIT cells and human asthma. The precise role of MAIT cells in asthma development and exacerbation, however, remains unknown. Our recently published work and additionally preliminary data indicate a striking anti-inflammatory role for MAIT cells in allergic airway inflammation. We hypothesize that a deficiency of MAIT cells in asthma patients contributes to exacerbated airway inflammatory responses to allergens, and that increasing MAIT cell numbers may help alleviate allergen-induced airway inflammation and hyperresponsiveness. Using fresh lung samples from deceased organ donors, we will examine the abundance and molecular properties of lung-resident MAIT cells in severe asthma patients and control individuals without lung diseases. We will use MAIT cell deficient mice and adoptive transfer strategies to interrogate the specific roles of MAIT cells in allergic airway inflammation. Finally, we will test whether boosting the number of MAIT cells by an engineered probiotic strain can help alleviate ongoing airway inflammation induced by common allergens.