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

Abstract

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.

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

“…At 42 d.p.i., we analyzed lung tissue B and T cell responses through intravenous (i.v.) injection of α-CD45 5 min before mouse sacrifice as we and others reported 40, 44, 45 . In this setting, CD45 i.v.…”

“…To confirm these observations, we sorted splenic T FH , lung CD4 + PD-1 Hi FR4 Hi or lung CD4 + PD-1 Low FR4 Low cells and performed Nanostring analysis of 560-immune associated genes without the need of RNA amplification 40 . Compared to lung CD4 + PD-1 Low FR4 Low cells, splenic T FH and lung CD4 + PD-1 Hi FR4 Hi cells expressed higher levels of T FH -associated genes including Bcl6, Sh2d1a and Tcf7 (Fig.…”

“…It has been shown before that CD8 + memory T cells against NP 366-374 or PA 224-233 epitope exhibit distinct phenotypic and recall properties 40, 48, 49, 50 . Specifically, lung CD8 + NP 366-374 memory T cells are highly protective and dominate over the CD8 + PA 224-233 memory T cells in the secondary recall expansion upon re-challenge with heterotypic influenza virus 40, 48, 49, 50 . We found that late CD4 + T cell depletion did not affect lung circulating or tissue CD8 + PA 224-233 memory T cell population (Fig.…”

“…Since CD8 + T RM (particularly NP 366-374 T RM 40 ) and possibly B RM cells are important in mediating host heterologous protection 5 , we next sought to determine whether the ablation of T RH cells impairs host protective immunity against heterologous virus infection. To do so, we employed a heterologous infection and challenge model in which X31 virus was used as the primary infection and lethal PR8 virus was used as secondary challenge 55 .…”

“…Based on their gene expression, sessile features and functional properties, we termed these cells tissue-resident T helper cells (T RH ). Importantly, T RH cells provide local help for the generation of strong B GC and B RM responses, as well as a CD8 + T RM population that is critical for the protection against heterologous influenza virus infection 39, 40 . We further identified the molecular cues mediating T RH cell help to B and CD8 + T cells.…”