Lung epithelial cell reprogramming by CD4 T cells

PROJECT SUMMARY Candidate Information: I am a postdoctoral fellow in Dr. Joseph Mizgerd’s lab at Boston University Pulmonary Center since Jan-2018 and my work has focused on elucidating how lung epithelial cells (LECs) and CD4 T cells communicate with each other to optimize bacterial clearance and tissue resilience during pneumococcal

pneumonia. My career objective is to become a tenure-track faculty member in a top-tiered academic institution, training scientists at all rungs of the academic ladder (including undergraduates, graduates, and postdocs) in investigating mechanisms- and consequences- of distinct cell-cell interactions on lung immunity and repair in

response to diverse infections, allergies, cancer and aging. To ensure that I make timely progress towards achieving my career objectives, I have put together a comprehensive plan comprised of short-, intermediate- and long- term research and training goals. I have gathered a mentoring team that will be comprised of Dr.

Joseph Mizgerd (Mentor) and Dr. Darrell Kotton (Co-mentor) and an advisory committee consisting of Dr. Jose Ordovas-Montanes, Dr. Carla Kim and Dr. Ulrich von Andrian that will ensure my continued training and progress towards proficiency in lung epithelial- and stem cell- biology, single cell sequencing and computational biology,

and pulmonary immunology along with a larger appreciation of cancer biology and T cell biology. All the committee members will regularly meet me in one-on-one discussion and larger committee meetings to ensure my rigorous research and career development training. This will aid my transition to independence with a unique

set of skills that empowers me to be a leader in the field of LEC-CD4 T cell crosstalk during health and disease. Proposed research and significance: Recurrent inhalation of microbes establishes lung-resident memory CD4 T (TRM) cells that confer anti-microbial immunity by remodeling LEC responses during reinfections. Our

preliminary data shows that LECs and stem cells are capable of antigen presentation to CD4 T cells during pneumonia and then harboring autonomous immune memory of their past encounters with CD4 T cells post resolution of pneumonia. Whether retrograde signaling that accompanies antigen presentation to CD4 T cells

reprograms concomitant and future LEC functions is unknown. Furthermore, the existence, epigenetic- and transcriptomic- extent, and consequences of LEC immune memory on subsequent LEC functions have never been investigated. Thus, the proposed studies will identify if engagement in an immune synapse remodels LEC

functions during pneumonia (K99) and will test if CD4 T cells generate trained immunity in LECs post resolution of pneumonia (R00). The proposed aims will involve use of single cell sequencing technology, novel genetically engineered mouse models, and innovative lineage tracing strategies to test whether CD4 T cells reprogram

LECs to preempt-, fight- and recover from- pneumonia. Findings will unify fields of mucosal immunity, LEC biology and lung regeneration and have the potential to identify LECs as immunomodulatory targets that can be trained to fight infections and cancers, promptly repair lungs, and to maintain pulmonary homeostasis.