cDC1-derived IL-27 regulates small intestinal CD4+ T cell homeostasis in miceAhmadi, Fatemeh;Junghus, Fredrik;Ashworth, Christian;Lappalainen, Amanda;Mörbe, Urs;Kotarsky, Knut;Agace, William W.
doi: 10.1084/jem.20221090pmid: 36515659
The small intestinal lamina propria contains large numbers of IFNγ-producing T helper (Th1) cells that play important roles in intestinal homeostasis and host defense, but the mechanisms underlying their development remain poorly understood. Here, we demonstrate that Th1 cells accumulate in the SI-LP after weaning and are maintained there long term. While both Th17 and Th1 cell accumulation in the SI-LP was microbiota dependent, Th1 cell accumulation uniquely required IL-27 and MHCII expression by cDC1. This reflected a requirement for IL-27 signaling in the priming of Th1 cells rather than for their maintenance once in the mucosa. cDC1-derived IL-27 was essential for maintaining the Th1–Th17 balance within the SI-LP, and in its absence, remaining Th1 cells expressed enhanced levels of Th17 signature genes. In conclusion, we identify cDC1-derived IL-27 as a key regulator of SI-LP Th1–Th17 cell homeostasis.
Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cellsKaiser, Katherine A.;Loffredo, Lucas F.;Santos-Alexis, Kenia de los;Ringham, Olivia R.;Arpaia, Nicholas
doi: 10.1084/jem.20221462pmid: 36534084
Following respiratory viral infection, regeneration of the epithelial barrier is required to preserve lung function and prevent secondary infections. Lung regulatory T (Treg) cells are critical for maintaining blood oxygenation following influenza virus infection through production of the EGFR ligand amphiregulin (Areg); however, how Treg cells engage with progenitors within the alveolar niche is unknown. Here, we describe local interactions between Treg cells and an Areg-responsive population of Col14a1+EGFR+ lung mesenchymal cells that mediate type II alveolar epithelial (AT2) cell-mediated regeneration following influenza virus infection. We propose a mechanism whereby Treg cells are deployed to sites of damage and provide pro-survival cues that support mesenchymal programming of the alveolar niche. In the absence of fibroblast EGFR signaling, we observe impaired AT2 proliferation and disrupted lung remodeling following viral clearance, uncovering a crucial immune/mesenchymal/epithelial network that guides alveolar regeneration.
B cell–intrinsic requirement for WNK1 kinase in antibody responses in miceHayward, Darryl A.;Vanes, Lesley;Wissmann, Stefanie;Sivapatham, Sujana;Hartweger, Harald;O’May, Joshua Biggs; de Boer, Leonard L.;Mitter, Richard;Köchl, Robert;Stein, Jens V.;Tybulewicz, Victor L.J.
doi: 10.1084/jem.20211827pmid: 36662229
Migration and adhesion play critical roles in B cells, regulating recirculation between lymphoid organs, migration within lymphoid tissue, and interaction with CD4+ T cells. However, there is limited knowledge of how B cells integrate chemokine receptor and integrin signaling with B cell activation to generate efficient humoral responses. Here, we show that the WNK1 kinase, a regulator of migration and adhesion, is essential in B cells for T-dependent and -independent antibody responses. We demonstrate that WNK1 transduces signals from the BCR, CXCR5, and CD40, and using intravital imaging, we show that WNK1 regulates migration of naive and activated B cells, and their interactions with T cells. Unexpectedly, we show that WNK1 is required for BCR- and CD40-induced proliferation, acting through the OXSR1 and STK39 kinases, and for efficient B cell–T cell collaboration in vivo. Thus, WNK1 is critical for humoral immune responses, by regulating B cell migration, adhesion, and T cell–dependent activation.
Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responsesHodge, Suzanne H.;Krauss, Maria Z.;Kaymak, Irem;King, James I.;Howden, Andrew J.M.;Panic, Gordana;Grencis, Richard K.;Swann, Jonathan R.;Sinclair, Linda V.;Hepworth, Matthew R.
doi: 10.1084/jem.20221073pmid: 36571761
Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens—including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 are found to be uniquely preprimed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine-producing capacity of ILC2. Mechanistically, amino acid uptake determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
Gut microbiota biofilms: From regulatory mechanisms to therapeutic targetsBuret, Andre G.;Allain, Thibault
doi: 10.1084/jem.20221743pmid: 36688957
Gut microbiota contain communities of viruses, bacteria, fungi, and Eukarya, and live as biofilms. In health, these biofilms adhere to the intestinal mucus surface without contacting the epithelium. Disruptions to the equilibrium between these biofilms and the host may create invasive pathobionts from these commensal communities and contribute to disease pathogenesis. Environmental factors appear to dominate over genetics in determining the shifts in microbiota populations and function, including when comparing microbiota between low-income and industrialized countries. The observations discussed herein carry enormous potential for the development of novel therapies targeting phenotype in microbiota dysbiosis.
Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibitionChu, Qiaoyun;An, Jing;Liu, Ping;Song, Yihan;Zhai, Xuewei;Yang, Ronghui;Niu, Jing;Yang, Chuanzhen;Li, Binghui
doi: 10.1084/jem.20221316pmid: 36520461
Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration–approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.
Tumor-derived OBP2A promotes prostate cancer castration resistanceJeong, Ji-Hak;Zhong, Shangwei;Li, Fuzhuo;Huang, Changhao;Chen, Xueyan;Liu, Qingqing;Peng, Shoujiao;Park, HaJeung;Lee, You Mie;Dhillon, Jasreman;Luo, Jun-Li
doi: 10.1084/jem.20211546pmid: 36547668
Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene–conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.