Innate lymphoid cells (ILCs), a heterogeneous cell population, are critical in orchestrating immunity and inflammation in the intestine, but whether ILCs influence immune responses or tissue homeostasis at other mucosal sites remains poorly characterized. Here we identify a population of lung-resident ILCs in mice and humans that expressed the alloantigen Thy-1 (CD90), interleukin 2 (IL-2) receptor a-chain (CD25), IL-7 receptor a-chain (CD127) and the IL-33 receptor subunit T1-ST2. Notably, mouse ILCs accumulated in the lung after infection with influenza virus, and depletion of ILCs resulted in loss of airway epithelial integrity, diminished lung function and impaired airway remodeling. These defects were restored by administration of the lung ILC product amphiregulin. Collectively, our results demonstrate a critical role for lung ILCs in restoring airway epithelial integrity and tissue homeostasis after infection with influenza virus.
SUMMARY
Exhausted CD8+ T cells function poorly and are negatively regulated by inhibitory receptors. Transcriptional profiling has identified gene expression changes associated with exhaustion. However, the transcriptional pathways critical to the differences between exhausted and functional memory CD8+ T cells are unclear. We thus defined transcriptional coexpression networks to define pathways centrally involved in exhaustion versus memory. These studies revealed differences between exhausted and memory CD8+ T cells including the following: lack of coordinated transcriptional modules of quiescence during exhaustion, centrally connected hub genes, pathways such as transcription factors, genes involved in regulation of immune responses, and DNA repair genes, as well as differential connectivity for genes including T-bet, Eomes, and other transcription factors. These data identify pathways involved in CD8+ T cell exhaustion, and highlight the context-dependent nature of transcription factors in exhaustion versus memory.
Summary
T cell exhaustion is common during chronic infections. While CD4+ T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and transcriptional program. We defined the phenotypic, functional and molecular profiles of exhausted CD4+ T cells. Global transcriptional analysis demonstrated a molecular profile distinct from effector or memory CD4+ T cells and also from exhausted CD8+ T cells, though some common features of CD4+ and CD8+ T cell exhaustion were revealed. We have demonstrated unappreciated roles for transcription factors (TFs) including Helios, type I interferon (IFN-I) signaling and a diverse set of co-inhibitory and costimulatory molecules during CD4+ T cell exhaustion. Moreover, the signature of CD4+ T cell exhaustion was found to be distinct from that of other CD4+ T cell lineage subsets and was associated with TF heterogeneity. This study provides a framework for therapeutic interventions targeting exhausted CD4+ T cells.
T cell exhaustion plays a major role in failure to control chronic infections. High expression of inhibitory receptors, including PD-1, and the inability to sustain functional T cell responses contribute to exhaustion. However, the transcriptional control of these processes remains unclear. Here we demonstrate that the transcription factor T-bet regulates CD8+ T cell exhaustion and inhibitory receptor expression. T-bet directly repressed Pdcd1 transcription and decreased the expression of other inhibitory receptors. While elevated T-bet promoted terminal differentiation following acute infection, high T-bet expression sustained exhausted CD8+ T cells and repressed inhibitory receptor expression during chronic viral infection. Persisting antigenic stimulation caused T-bet downregulation, which resulted in more severe exhaustion of CD8+ T cells. These observations suggest therapeutic opportunities involving increasing T-bet expression during chronic infection.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.