Rapid IFNg production by CD8+ TRM slows viral propagation but is insufficient to directly mediate clearance following respiratory virus transmission 2260225

Abstract

Abstract Introduction Tissue-resident memory CD8+ T cells (TRM) in the respiratory tract can restrict viral spread and protect against transmission through secretion of IFN-gamma (IFNg), however, the precise mechanisms by which TRM-derived IFNg limits viral transmission remains poorly defined. We aimed to determine how IFNg alone, in the absence of other TRM-mediated effector mechanisms, contributes to protection against respiratory virus transmission Methods Using a natural mouse model of Sendai virus (SeV) transmission and bioluminescence imaging of viral dynamics, we developed an approach to activate WT or Ifng-/- influenza-specific TRM during SeV exposure to assess whether IFNg production from bystander, non-SeV-specific TRM in the upper respiratory tract (URT) could protect against developing a productive SeV infection. Results Activation of bystander TRM in the URT during SeV exposure significantly delayed viral propagation, and in some cases prevented productive SeV infection, in an IFNg-dependent manner. Using different immunization strategies, we found that the magnitude of this effect positively correlated by bystander TRM number. Bystander IFNg production enhanced early recruitment of SeV-specific T cells from circulation, rapidly induced antiviral programming in URT epithelial cells, and boosted local inflammatory cytokines. Notably, the ability of bystander TRM-derived IFNg to prevent infection was lost when the recruitment of pre-existing or de novo SeV-specific T cells from circulation was inhibited. Conclusion Overall, our data suggest that the primary role for rapid IFNg production during transmission is to reduce viral propagation in order to “buy time” for other effector mechanisms to mediate viral clearance. Understanding how different TRM effector mechanisms are coordinated to optimize viral clearance while limiting immunopathology will assist in the design of mucosal vaccines that provide broad, cross-protective immunity against respiratory viruses. Funding Source R01 AI190367 and R35 HL150803 Topic Categories Viral Immunology (VIR)