Understanding Dysregulated Crosstalk Between Regulatory T Cells and Lung Dendritic Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease

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Chronic obstructive pulmonary disease (COPD) is a highly prevalent lung disease and is the 4th leading cause of death in the world. COPD results from inhalation of oxidants, such as cigarette smoke, which causes inflammatory cell infiltration and lung destruction. COPD is a progressive disease leading to significant morbidity and mortality. There are no therapies to halt the decline in lung function. Our long-term goal is to understand the mechanisms underlying COPD pathogenesis so that we can develop an immunotherapy to stop disease progression. T regulatory cells (Tregs) decreased in the lungs of smokers with COPD compared to smokers without COPD. Lung dendritic cells (DCs), which are able to polarize T cells to become Tregs or T effector cells (Teff), are more mature in COPD, suggesting that they have a pro-inflammatory as opposed to a tolerogenic phenotype. We hypothesize that in COPD, the increased number of mature pro-inflammatory DCs are driving T cells towards Teff phenotype, whereas under normal conditions, tolerogenic DCs would be more likely to promote induction of Tregs. In return, Tregs can modulate DC phenotype and function, suggesting that subtle crosstalk feedback mechanisms are involved in the regulation of DC and Treg. However, no studies have looked at whether dysregulated crosstalk between Treg and DC populations contributes to COPD pathogenesis. Our specific aims are: 1) to demonstrate that COPD is associated with a shift from tolerogenic to pro-inflammatory DCs; 2) to show that pro-inflammatory DCs preferentially polarize T cells towards a Teff phenotype compared to tolerogenic DCs; and 3) to provide evidence that the transfer of Tregs will restore the number of tolerogenic DCs in the lung. This proposal will utilize an established murine cigarette-smoke based COPD model and also excess human lung tissue from consented patients undergoing clinically-indicated lung surgeries, both with and without COPD. This allows us to conduct translational research and take observations from human samples to the mouse model where we can answer more mechanistic questions. Despite the abundance of clinical trials related to Treg therapy, there are currently no similar trials looking at Tregs in patients with COPD. Successful completion of this proposal will fill critical gaps in knowledge and provide pre-clinical data in support of exploring Treg therapy for COPD patients. This proposal will take place with the combined resources of the University of Michigan and the VA Ann Arbor Healthcare System (the physical location of the laboratory). There are world-class facilities at both locations. The VA houses a murine smoke-exposure facility, Microscopy Core, and FACSAria sorter, and all equipment and space needed to conduct the research. Many members of the Immunology Graduate Program have labs at the VA, making for a robust scientific environment. The training plan developed to successfully complete this proposal includes advanced training in acquisition and analysis of fluorescent microscopy images, laboratory-specific training for the study of lung leukocytes, and training in human research protections and the analysis of human data.