2025 Theses Doctoral

Mechanisms of Lung-localized Protection to Respiratory Viruses By Tissue Resident Memory T Cells

Yang, Alexander

Respiratory viruses such as influenza A virus (IAV) and SARS-CoV-2 are highly ubiquitous and contagious pathogens responsible for pandemics and seasonal epidemics, posing a constant threat to human health worldwide. Upon infection, respiratory viruses elicit potent inflammatory responses to recruit adaptive B and T cells which work together to mediate viral clearance. Afterwards, long-lived memory B and T cells confer lasting protection from reinfection; however, respiratory viruses like IAV and SARS-CoV-2 exhibit high mutation rates that facilitate the evasion of antibody-mediated neutralization. We and others have shown that tissue resident memory T cells (T_RM), a subset of memory T cells that reside at the site of previous infection, and not circulating memory T cells, mediate rapid and robust cross-strain protection to subsequent respiratory viral challenge resulting in enhanced viral clearance and significantly reduced morbidity and mortality. However, the mechanisms by which T_RM orchestrate the induction of a carefully balanced protective inflammatory response while safeguarding from excessive inflammation and immunopathology remain poorly understood.

To elucidate the mechanisms for T_RM-mediated protection, we utilized a murine model of heterosubtypic IAV infection demonstrating that T_RM fundamentally alter the induction of the lung-localized immune response to secondary respiratory viral infection. In comparison to primary responses, which were initiated by potent inflammatory innate immune pathways, secondary responses were characterized by a relatively attenuated innate immune response and a unique induction of adaptive immune pathways associated with T cell activation.

Further dissection of the molecular mediators revealed a unique upregulation of 𝐼𝑙-10 in secondary responses. Using a reporter mouse, we identified that lung T_RM are the principal producers of IL-10 during respiratory challenge. Inhibition of early IL-10 signaling in secondary infection resulted in increased morbidity and lung pathology with no effect on viral clearance. Further dissection on the effects of early IL-10 in secondary infections revealed a pleiotropic effect in regulating macrophage inflammation and enhancing IFN-𝛄 production by memory CD8⁺T cells.

To extend these findings to humans, we utilized a unique human tissue resource in collaboration with the New York City organ procurement organization, LiveOnNY in which we characterized the flu-specific response in human blood, spleen, lung, and lung-draining lymph node. Cellular indexing of transcriptomes and epitopes (CITE-Seq) analysis revealed that human influenza-reactive T_RM and not circulating memory produce IL-10, mirroring our results in our murine model of IAV infection. Human IL-10-producing T_RM also exhibited polyfunctional effector functions by also producing IFN-𝛄. These data elucidate a dual function for T_RM in coordinating 𝘪𝘯 𝘴𝘪𝘵𝘶 secondary responses by amplifying antiviral responses for robust viral clearance while dampening excessive inflammation to limit tissue damage and immunopathology.