Chronic Obstructive Pulmonary Disease (COPD) is now the 3rd leading cause of death in the United States, and the only cause of death that is on the rise. Smoking is the most common risk factor for COPD, however thereareotherenvironmentaltriggerssuchasdust,smoke,sand,oraerosols.NearlyoneintenVApatients arediagnosedwithCOPDandthecostsassociatedwiththesepatientsaretentimeshigherthanforallother conditions. Despite the prevalence of COPD, our understanding of the immune mechanisms that drive developmentofthediseaseisincomplete.ThereisincreasingevidencethatcytotoxicCD8+Tcellsarecritical tothepathologyofCOPD.WorkdonebythePIandcollaboratorshasidentifiedmucosalassociatedinvariant T(MAIT)cellsasan?innate?-likelung-residentCD8+Tcellpopulationcapableofrecognizingairwayepithelial cellsinfectedwithCOPD-associatedlungpathogens.Althoughlowerairwaybacterialinfectionsareassociated with COPD and are correlated with airway function, the mechanisms by which infections develop and contribute to COPD pathogenesis is not yet clear. Because CD8+ T cells recognize and destroy target cells infected with pathogens, lung-resident CD8+ T cells like MAIT cells may be important for containment of bacterialinfections.Infact,wefindthatMAITcells,whicharehighlyenrichedinhumanairways,havereduced frequency in the peripheral blood of COPD patients. Furthermore, we find that MAIT cells, while capable of controllingthegrowthofbacteria,areimpairedintheirabilitytomakeIFN-g?inresponsetobacteriallyinfected airway epithelial cells from patients with COPD. The effect of COPD on MAIT cell function is not known and may be essential to understanding how lower respiratory infections contribute to the development of COPD andCOPDexacerbations. ThisproposalisfocusedondeterminingthemechanismsbywhichCOPDaltersthefrequencyandfunctionof MAITcells,particularlywithregardtorecognitionofbacteriallyinfectedairwayepithelialcells.Additionally,we willdeterminetheconsequencesofalteredMAITcellactivationonbacterialsurvivalandinflammation. ThisprojectcontainstwoAims:
Aim 1. Define the frequency and functional capacity of MAIT cells among CD8+ T cells from COPD lungs.
Aim 2. Define the mechanisms underlying MAIT cell-mediated killing of bacteria, and how these mechanismsaremodulatedinCOPD.
Chronic obstructive pulmonary disease (COPD) has become the 3rd leading cause of death in the United States and is a problem of particular concern among the Veteran population. COPD is characterized by irreversible airflow obstruction due to inflammation, and a better understanding of the cellular mechanisms underlying this inflammation will provide direct application to the development of more targeted and efficient treatment strategies. This application is focused on understanding how MAIT cells, a unique population of lung- resident human CD8+ T cells, contribute to inflammation and lower airway infections in COPD.