Research ArticleT CELLS

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

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Science Immunology  14 Jun 2019:
Vol. 4, Issue 36, eaaw1217
DOI: 10.1126/sciimmunol.aaw1217

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Keeping T cells on a tight leash

Using influenza virus (IAV) as a model, Wang et al. have examined the ability of CD8+ T cells recognizing two epitopes of IAV, nucleoprotein peptide 366–374 (NP366–374) and polymerase peptide 224–233 (PA224–233), to give rise to resident memory T (TRM) cells in the lung. Although CD8+ T cell responses to both epitopes are comparable in primary infection, previous studies have shown NP366–374-specific responses to be dominant upon reinfection. Here, Wang et al. found that NP366–374-specific TRM cells express higher levels of PD1 and become more exhausted-like when compared with PA224–233-specific TRM cells after viral clearance, allowing them to be reactivated upon reinfection. Further, they show that maintenance of NP366–374-specific TRM in an exhausted-like state prevents inflammation-induced lung fibrosis.


CD8+ tissue-resident memory T (TRM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8+ TRM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8+ TRM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These TRM 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 TRM 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 TRM cells at the memory phase. Our data indicate that TRM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.

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