Linzheng (Ling) Shi: BME PhD Defense

Title: " LUNG-RESIDENT IMMUNITY GOVERNS EARLY PNEUMONIA DEFENSE REVEALED BY PARACORPOREAL CRYSTAL RIBCAGE"

Advisory Committee: Béla Suki, Ph.D. (Chair) Hadi T. Nia, Ph.D. (Advisor) Joseph P. Mizgerd, Sc.D. Christopher C. Chen, M.D., Ph.D. Elliot Chaikof, M.D., Ph.D.

Abstract: Pneumonia remains a leading cause of morbidity and mortality worldwide. Immune history strongly influences disease incidence and severity, yet the underlying mechanisms remain poorly defined. A central challenge is to disentangle how prior infections remodel pulmonary (lung-resident) versus systemic (circulatory-borne) immunity, and to determine how changes in each compartment shape the host response to subsequent infections. To address this challenge, we developed the paracorporeal crystal ribcage, an immunocompetent murine cross-circulation platform that perfuses blood from a freely behaving “donor” mouse to isolated functioning “recipient” lungs housed inside the crystal ribcage for real-time cellular imaging across long-term (24 hour) durations. By mismatching immune histories between donor and recipient, e.g., perfusing blood from immune experienced mice through naïve lungs, and vice versa, we mechanistically dissected the contributions of systemic and pulmonary immune components to the defense against pneumonia. Our findings revealed that the accelerated neutrophil recruitment in experienced lungs is mediated by lung CD4+ resident memory T cells, not by modifications to neutrophils or their precursors in the bone marrow, nor by T cells from the blood and secondary lymphoid organs. We further developed a parallel recipient model enabling side-by-side visualization of cellular dynamics in experienced versus naïve lungs sharing a common circulation. Coupled with high-dimensional quantitative analyses, this approach revealed distinct alveolar macrophage motility signatures associated with trained innate immunity. Together, these results demonstrate that adaptive and innate immune remodeling within the lung underlies the enhanced protection observed after prior infections, with important implications for the design and delivery of effective therapeutics and vaccines. They further establish the paracorporeal crystal ribcage as a versatile platform for studying systemic versus pulmonary immunity across diverse conditions.