Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus.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.
Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virusThe transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsetsCyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in miceHai Ni, Yinuo Wang, Kai Yao et al.|Nature Communications|2024 Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.
Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8 <sup>+</sup> T cell metabolic fitness and function in tumorsJiefeng Yang, Jiefeng Yang, Xudong Xing et al.|Science Immunology|2023 Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8 + T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8 + T cells, MFN2 enhances mitochondria–endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca 2+ -ATPase SERCA2, facilitating the mitochondrial Ca 2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca 2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca 2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8 + T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8 + T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.