Impact of Regulatory T Cells on Host Susceptibility to Pseudomonas Aeruginosa Infection - PROJECT SUMMARY Regulatory T cells (Tregs) are a subset of CD4+ T lymphocytes that control inflammatory signaling in mucosal tissues. Tregs mitigate the release of pro-oxidant molecules by leukocytes, which protects the affected organ from self-inflammatory damage. One of the major mechanisms by which Tregs suppress host inflammation is via producing the nucleoside adenosine, which is generated by the ectonucleotidase CD73. In individuals lacking either Tregs or CD73 signaling, such as those suffering from certain autoimmune pathologies, there is substantial tissue destruction by effector leukocytes, confirming the clinical relevance of these pathways. However, the role of Tregs in other inflammatory settings, such as bacterial pneumonia, is poorly understood. Here, we present with strong preliminary data indicating that Tregs protect from pulmonary infection by Pseudomonas aeruginosa, which is a prominent human pathogen that thrives in inflamed mucosae. The mechanism by which P. aeruginosa persists in inflamed tissues is via production of biofilms in response to oxidative metabolites released by leukocytic cells. We postulated that the mechanism by which Tregs restrict P. aeruginosa pneumonia is through limitation of airway metabolites that fuel pathogen survival. In Aim 1 of this proposal, we will evaluate whether Tregs protect from P. aeruginosa pneumonia by altering the airway metabolome composition, reducing accumulation of metabolites that drive bacterial both biofilm lifestyle and growth. In Aim 2, we will assess whether this regulation is promoted by adenosine signaling, particularly through CD73 expression in Tregs. The findings of this project will reveal a new pathway, Tregs, as a new potential target to control intractable P. aeruginosa lung disease.
