PD-1 ^hi CD8 ⁺ resident memory T cells balance immunity and fibrotic sequelae

Abstract

CD8⁺ tissue-resident memory T (T_RM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8⁺ T_RM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8⁺ T_RM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These T_RM cells have both exhausted-like phenotypes and memory features and provide heterologous immunity against secondary infection. PD-L1 blockade after the resolution of primary infection promotes the rejuvenation of these exhausted-like T_RM cells, restoring protective immunity at the cost of promoting postinfection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of exhausted-like T_RM cells at the memory phase. Our data indicate that T_RM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.