Citations

Abstract Alveolar Macrophages (AMs) are unique innate immune cells that reside in the alveolar space and accommodate the ever-changing need of the lungs against internal and external challenges. During homeostasis, AMs maintained themselves through self-renewal without the need for input from adult hematopoietic stem cells. Currently, little is known about how aging influences AM dynamics, heterogeneity and self-renewal. To this end, we have performed single-cell RNA sequencing (scRNA-seq) on murine lung AMs (CD11+ Siglec F+) isolated from young (~8w) and aged (~2y) mice. We discovered that despite similar transcriptome in the proliferating cells, AMs from aged mice had reduced proliferation and self-renew ability than those from the young mice. AMs from aged mice also displayed elevated senescence markers such as p16, p21 and p53. Consistently, AMs from aged mice had reduced DNA repair ability, which could contribute to their impaired capacity to pass through the cell cycle checkpoints. Interestingly, AMs from aged mice also possessed reduced pro-apoptotic gene profile. Thus, we hypothesize that the reduced proliferation- and apoptosis-associated gene profiles in aged AMs may lead to the enhanced senescence-like phenotype in those cells. Further validation of the senescence-like phenotype of aged AMs and investigation of how they contribute to lung “inflammaging” are warranted.

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 co-stimulation after acute influenza infection. These TRM cells have both “exhausted-like” phenotypes and memory features, and provide heterologous immunity against secondary infection. Using recombinant influenza virus, we demonstrate that the development of these PD-1hi “exhausted-like” TRM cells is dependent on the doses of the antigen during primary infection. Furthermore, we showed that lung CD11c+ antigen presenting cells are required for sustaining these TRM cells at the memory stage. Our data suggest that continuous antigen presentation in situ is required for the development and maintenance of these “exhausted-like” TRM cells in the lung. Strikingly, 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 post-infection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of “exhausted-like” TRM cells at the memory phase under specific tissue environment with chronic low-levels of antigen presentation following viral clearance. Our data indicate that TRM cell “exhaustion” is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.

Abstract Tissue-resident memory CD8+ T cells (TRM) share characteristics and core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic and epigenetic regulation of TRM and TIL differentiation, maintenance and function are largely undefined. Furthermore, it is unknown whether metabolic and epigenetic manipulations can be employed to promote TRM/TIL functional programs for cancer immunotherapy. Here we report a critical mechanism programming the mitochondrial and epigenetic regulation of TRM/TIL functionality in situ. We find that mouse and human TRM/TIL express the transcription factor BHLHE40 and the BHLHE40-associated gene signature. Bhlhe40 is specifically required for TRM and TIL development and poly-functionality. Local PD-1 signaling inhibits TIL Bhlhe40 expression, and Bhlhe40 is critical for TIL reinvigoration following anti-PD therapy. Mechanistically, Bhlhe40 sustains TRM/TIL mitochondrial fitness for the promotion of a functional epigenetic state. Building on these findings, we also identify an epigenetic and metabolic regimen that promotes TRM/TIL gene signatures associated with tissue residency and poly-functionality through in vitro T cell screening. Strikingly, this regimen empowers the anti-tumor activity of CD8+ T cells and possesses therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights on the local regulation of TRM and TIL function, and offer a viable strategy for developing novel immunotherapeutic means for cancer.

Respiratory tissue resident–like CD8 + T cells are associated with chronic lung sequelae post-acute COVID-19.

Identification of a CD4 + helper T cell population providing in situ help to B and CD8 + T cells in the respiratory mucosa.

Age-associated T RM cell malfunction supports chronic lung inflammation and tissue fibrosis after respiratory viral infection.

RXRA is an endothelial- and early stage–predominant therapeutic target for treating anthracycline-induced cardiotoxicity.

Exhausted-like CD8 + resident memory T cells in the lung limit immune activation–driven fibrosis.

Long intergenic non-coding RNA (lincRNA) is a family of gene transcripts, the functions of which are largely unknown. Although cigarette smoking is the main cause for lung cancer, lung cancer in non-smokers is a separate entity and its underlying cause is little known. Growing evidence suggests lincRNAs play a significant role in cancer development and progression; however, such data is lacking for lung cancer in non-smokers, or those who have never smoked. This study conducted comprehensive profiling of lincRNAs from RNA sequencing (RNA-seq) data of non-smoker patients with lung adenocarcinoma. Both known and novel lincRNAs distinctly segregated tumors from normal tissues. Approximately one third of lincRNAs were differentially expressed between tumors and normal samples and most of them were coordinated with their putative protein gene targets. More importantly, lincRNAs defined two clusters of tumors that were associated with tumor aggressiveness and patient survival. We identified a subset of lincRNAs that were differentially expressed and also associated with patient survival. Very high concordance (R2 = 0.9) was observed for the differentially expressed lincRNAs in the Cancer Genome Atlas (TCGA) validation set of 85 transcriptomes and the lincRNAs associated with survival from the discovery set were similarly predictive in the validation set. These lincRNAs warrant further investigation as potential diagnostic and prognostic markers.

Abstract IFN regulatory factor 4 (IRF4) is a key transcription factor that promotes effector CD8+ T cell differentiation and expansion. The roles of IRF4 in regulating the CD8+ T cell response to cytokines have not been explored. In this article, we show that IL-2 and IL-15 signaling and STAT5 activation regulate IRF4 expression in CD8+ T cells. Gene-expression profile analysis has also revealed that IRF4 is required for expression of the receptors of IL-2 family cytokines CD122 and CD127. We found that IRF4 binds directly to CD122 and CD127 gene loci, indicating that it may directly promote CD122 and CD127 gene transcription. As a consequence, IRF4-deficient CD8+ T cells show diminished sensitivity to IL-2, IL-15, and IL-7 treatment in vitro. Furthermore, we found that IRF4-deficient CD8+ T cells had lower expression of CD122 and CD127 in vivo during influenza virus infection. These data suggest that IRF4 regulates the sensitivity of CD8+ T cells to IL-2 family cytokines, which correlates with the diminished effector and memory CD8+ T cell responses in IRF4-deficient CD8+ T cells.