Wang, Zheng

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.

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.

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.