Differential requirements for cytokine signaling and local antigen in upper versus lower respiratory tract CD8+ TRM development.

CD8+ tissue-resident memory T cells (TRM) in the upper respiratory tract (URT) limit viral replication after transmission and prevent spread to the lower respiratory tract (LRT), whereas LRT CD8+ TRM are important for limiting immunopathology in the lung and promoting efficient viral clearance. Although the presence of local respiratory antigen is thought to be required for CD8+ TRM development in the LRT but not the URT, the relationship between local antigen encounter and cytokine signaling that influences TRM differentiation in distinct niches of the respiratory tract remains unknown. Here, we show using murine models that while URT TRM generated in the presence or absence of local respiratory antigen are phenotypically, transcriptionally, and functionally similar throughout the respiratory tract, their developmental pathways are compartmentally distinct and characterized by a context-dependent compensatory relationship between antigen and cytokine signaling. In the absence of local antigen, URT CD8+ TRM formation required TGF-β signaling, and notably, while both IL-15 and IL-33 were broadly dispensable in the URT, IL-33 was able to rescue LRT CD8+ TRM development in the absence of local antigen. Together, these findings highlight key differences for CD8+ TRM development in distinct areas of the respiratory tract, offering valuable insights into the development of mucosal cellular immunity following intranasal and parenteral vaccination.