Xin Geng, Lijuan Chen, Zoheb Ahmed, Guilherme Pedron Formigari, Yen-Chun Ho, Ilaria Del Gaudio, Marcella Neves Datilo, Zheila J Azartash-Namin, Coraline Heron, Xindi Shan, Ravi Shankar Keshari, Soumiya Pal, Hong Chen, Florea Lupu, Lijun Xia, Gwendalyn J Randolph, Scott D Zawieja, Eric Camerer, Michael J Davis, R Sathish Srinivasan
{"title":"S1PR1 regulates lymphatic valve development and tertiary lymphoid organ formation in the ileum.","authors":"Xin Geng, Lijuan Chen, Zoheb Ahmed, Guilherme Pedron Formigari, Yen-Chun Ho, Ilaria Del Gaudio, Marcella Neves Datilo, Zheila J Azartash-Namin, Coraline Heron, Xindi Shan, Ravi Shankar Keshari, Soumiya Pal, Hong Chen, Florea Lupu, Lijun Xia, Gwendalyn J Randolph, Scott D Zawieja, Eric Camerer, Michael J Davis, R Sathish Srinivasan","doi":"10.1084/jem.20241799","DOIUrl":"10.1084/jem.20241799","url":null,"abstract":"<p><p>Efficient lymph flow is ensured by lymphatic valves (LVs). The mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal ileum-draining lymphatic vessels were specifically dysfunctional. Furthermore, tertiary lymphoid organs (TLOs) formed in the terminal ileum of the mutant mice. TLOs in this location are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Mechanistically, S1PR1 regulates shear stress signaling and the expression of the valve-regulatory molecules FOXC2 and connexin-37. Importantly, Foxc2+/- mice, a model for lymphedema-distichiasis syndrome, also develop TLOs in the terminal ileum. Thus, we have discovered S1PR1 as a previously unknown regulator of LV and TLO development. We also suggest that TLOs are a sign of subclinical inflammation that can form due to lymphatic disorders in the absence of ileitis.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12187108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aneesha Dasgupta, Rebecca E Schmitt, Tatsuyoshi Kono, Chih-Chun Lee, Mark I Zoberi, Savannah A Epstein, Jessica Z Schneider, Alejandro Hernandez, Paul M Grandgenett, Thomas C Caffrey, Dominick J DiMaio, Michael A Hollingsworth, Jason D Doles
{"title":"Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.","authors":"Aneesha Dasgupta, Rebecca E Schmitt, Tatsuyoshi Kono, Chih-Chun Lee, Mark I Zoberi, Savannah A Epstein, Jessica Z Schneider, Alejandro Hernandez, Paul M Grandgenett, Thomas C Caffrey, Dominick J DiMaio, Michael A Hollingsworth, Jason D Doles","doi":"10.1084/jem.20242239","DOIUrl":"10.1084/jem.20242239","url":null,"abstract":"<p><p>Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at ∼80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by α-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12237250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CD4+ T cell dysfunction in cancer.","authors":"Hrishi Venkatesh, Lawrence Fong","doi":"10.1084/jem.20241417","DOIUrl":"https://doi.org/10.1084/jem.20241417","url":null,"abstract":"<p><p>While the importance of CD8+ T cells in successful cancer immunotherapy is well-established, CD4+ T cells are increasingly recognized as key mediators of effective anti-tumor immunity. However, the mechanisms underlying the functional impairment of CD4+ T cells in tumors are not as well characterized as in CD8+ T cells. In this review, we will explore how CD4+ T cells are altered in tumor-bearing hosts, compare these changes to those observed in CD8+ T cells, and discuss how these changes impact tumor control. Approaches that counteract functional impairment in tumor-reactive CD4+ T cells may further enhance the efficacy of cancer immunotherapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lipid metabolism and neuroinflammation: What is the link?","authors":"Vini Tiwari, Mikael Simons","doi":"10.1084/jem.20241232","DOIUrl":"https://doi.org/10.1084/jem.20241232","url":null,"abstract":"<p><p>Lipid metabolism is central to host defense by supporting and modulating immune cell function. Immune signaling pathways control anabolic lipid processes to drive membrane synthesis and produce bioactive lipid mediators during activation. In turn, metabolic states profoundly influence immune signaling, particularly during the resolution of inflammation. Emerging evidence highlights a dynamic interplay between lipid metabolism and neuroinflammation. A striking example is the intrinsic lipoprotein system of the central nervous system, which undergoes profound changes during pathology, with lipoproteins serving not only in lipid transport but also as immune modulators and as contributors to disease tolerance. Importantly, major neurodegenerative diseases are genetically linked to disruptions in lipid metabolism. Deciphering this complex cross talk may provide opportunities for novel therapies targeting neuroinflammatory and neurodegenerative disorders.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Åsa Johansson, Mahadevan Venkita Subramani, Bahtiyar Yilmaz, Elisabeth E L Nyström, Elena Layunta, Liisa Arike, Felix Sommer, Philip Rosenstiel, Lars Vereecke, Louise Mannerås-Holm, Andy Wullaert, Thaher Pelaseyed, Malin E V Johansson, George M H Birchenough
{"title":"Neonatal microbiota colonization primes maturation of goblet cell-mediated protection in the pre-weaning colon.","authors":"Åsa Johansson, Mahadevan Venkita Subramani, Bahtiyar Yilmaz, Elisabeth E L Nyström, Elena Layunta, Liisa Arike, Felix Sommer, Philip Rosenstiel, Lars Vereecke, Louise Mannerås-Holm, Andy Wullaert, Thaher Pelaseyed, Malin E V Johansson, George M H Birchenough","doi":"10.1084/jem.20241591","DOIUrl":"10.1084/jem.20241591","url":null,"abstract":"<p><p>Regulated host-microbe interactions are a critical aspect of lifelong health. Colonic goblet cells protect from microorganisms via the generation of a mucus barrier structure. Bacteria-sensing sentinel goblet cells provide secondary protection by orchestrating mucus secretion when microbes breach the mucus barrier. Mucus deficiencies in germ-free mice implicate a role for the microbiota in programming barrier generation, but its natural ontogeny remains undefined. We now investigate the mucus barrier and sentinel goblet cell development in relation to postnatal colonization. Combined in vivo and ex vivo analyses demonstrate rapid and sequential microbiota-dependent development of these primary and secondary goblet cell protective functions, with dynamic changes in mucus processing dependent on innate immune signaling via MyD88 and development of functional sentinel goblet cells dependent on the NADPH/dual oxidase family member Duox2. Our findings identify new mechanisms of microbiota-goblet cell regulatory interaction and highlight the critical importance of the pre-weaning period for the normal development of protective systems that are key legislators of host-microbiota interaction.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Endi K Santosa, Jennifer M Zhang, John C Sauter, Mariah E Lee, Brandon D Ng, Sigrun V Stulz, Meril Takizawa, Simon Grassmann, Orr-El Weizman, Nicholas M Adams, Ronan Chaligné, Annette Oxenius, Georg Gasteiger, Colleen M Lau, Joseph C Sun
{"title":"Defining molecular circuits of CD8+ T cell responses in tissues during latent viral infection.","authors":"Endi K Santosa, Jennifer M Zhang, John C Sauter, Mariah E Lee, Brandon D Ng, Sigrun V Stulz, Meril Takizawa, Simon Grassmann, Orr-El Weizman, Nicholas M Adams, Ronan Chaligné, Annette Oxenius, Georg Gasteiger, Colleen M Lau, Joseph C Sun","doi":"10.1084/jem.20242078","DOIUrl":"10.1084/jem.20242078","url":null,"abstract":"<p><p>Latent viral infections rely on a precise coordination of the immune response to control sporadic viral reactivation. CD8+ T cells play a crucial role in controlling viral latency by generating diverse memory responses in an epitope-specific manner. Among these distinct responses, conventional and inflationary memory responses have been described during herpesvirus infections. Using a newly generated TCR transgenic mouse strain, we investigated the transcriptomic and epigenetic remodeling of distinct epitope-specific CD8+ T cells during CMV infection across tissues at both population and single-cell levels. Our findings reveal that whereas the transcriptomic and epigenetic landscapes of conventional and inflationary memory responses diverge in the spleen and liver, these molecular programs converge in the salivary gland, a site of CMV persistence. Thus, we provide evidence that the dynamics of memory CD8+ T cell responses are distinct between tissues.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chuangyu Wen, Emile Z Naccasha, Chuan He, Hua Laura Liang, Ralph R Weichselbaum
{"title":"YTHDFs as radiotherapy checkpoints in tumor immunity.","authors":"Chuangyu Wen, Emile Z Naccasha, Chuan He, Hua Laura Liang, Ralph R Weichselbaum","doi":"10.1084/jem.20250272","DOIUrl":"10.1084/jem.20250272","url":null,"abstract":"<p><p>Radiotherapy (RT), a cornerstone of cancer treatment, exerts its therapeutic effects primarily by inducing DNA damage in tumor cells and modulating the tumor immune microenvironment (TIME). Despite its efficacy, RT is often counteracted by tumor-intrinsic mechanisms, such as DNA damage repair, as well as immune-suppressive responses. YTHDF proteins, key N6-methyladenosine (m6A) readers, have emerged as pivotal regulators of tumor progression, DNA repair, and immune cell function, making them promising targets for enhancing RT efficacy. In this review, we explore the dual roles of YTHDF proteins in modulating both tumor-intrinsic and immune-mediated responses to RT. We summarize their influence on DNA damage repair pathways in tumor cells and their impact on the TIME, which collectively shape the antitumor efficacy of RT. Furthermore, we discuss recent advances in the development of YTHDF-targeting inhibitors and their potential to synergize with RT and immunotherapy, offering new avenues to improve cancer treatment outcomes.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12139520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, Sophie Panigot, Daiki Mori, Liaoxun Lu, Guillaume Voisinne, Carine Vilarnau Wolek, Marielle Mello, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Frédéric Fiore, Romain Roncagalli, Yinming Liang, Marie Malissen, Bernard Malissen
{"title":"A CARMIL2 gain-of-function mutation suffices to trigger most CD28 costimulatory functions in vivo.","authors":"Fanghui Zhang, Javier Celis-Gutierrez, Lichen Zhang, Valentin Mellado, Léna Gelard, Sophie Panigot, Daiki Mori, Liaoxun Lu, Guillaume Voisinne, Carine Vilarnau Wolek, Marielle Mello, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Frédéric Fiore, Romain Roncagalli, Yinming Liang, Marie Malissen, Bernard Malissen","doi":"10.1084/jem.20250339","DOIUrl":"10.1084/jem.20250339","url":null,"abstract":"<p><p>Naive T cell activation requires both TCR and CD28 signals. The CARMIL2 cytosolic protein enables CD28-dependent activation of the NF-κB transcription factor via its ability to link CD28 to the CARD11 adaptor protein. Here, we developed mice expressing a mutation named Carmil2QE and mimicking a mutation found in human T cell malignancies. Naive T cells from Carmil2QE mice contained preformed CARMIL2QE-CARD11 complexes in numbers comparable to those assembling in wild-type T cells after CD28 engagement. Such ready-made CARMIL2QE-CARD11 complexes also formed in CD28-deficient mice where they unexpectedly induced most of the functions that normally result from CD28 engagement in a manner that remains antigen-dependent. In turn, tumor-specific T cells expressing Carmil2QE do not require CD28 engagement and thereby escape to both PD-1 and CTLA-4 inhibition. In conclusion, we uncovered the overarching role played by CARMIL2-CARD11 signals among those triggered by CD28 and exploited them to induce potent solid tumor-specific T cell responses in the absence of CD28 ligands and immune checkpoint inhibitors.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12097149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Riccardo Castagnoli, Francesca Pala, Poorani Subramanian, Cihan Oguz, Benjamin Schwarz, Ai Ing Lim, Andrew S Burns, Elena Fontana, Marita Bosticardo, Cristina Corsino, Angelina Angelova, Ottavia M Delmonte, Heather Kenney, Deanna Riley, Grace Smith, Lisa Ott de Bruin, Vasileios Oikonomou, Lucas Dos Santos Dias, Danielle Fink, Eric Bohrnsen, Cole D Kimzey, Gian Luigi Marseglia, Guisela Alva-Lozada, Jenna R E Bergerson, Ana Brett, Karlla W Brigatti, Dimana Dimitrova, Cullen M Dutmer, Alexandra F Freeman, Hanadys Ale, Steven M Holland, Francesco Licciardi, Srdjan Pasic, Laura E Poskitt, David E Potts, Joseph F Dasso, Svetlana O Sharapova, Kevin A Strauss, Brant R Ward, Melis Yilmaz, Douglas B Kuhns, Michail S Lionakis, Stephen R Daley, Heidi H Kong, Julia A Segre, Anna Villa, Stefania Pittaluga, Jolan E Walter, Ivan Vujkovic-Cvijin, Yasmine Belkaid, Luigi D Notarangelo
{"title":"Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency.","authors":"Riccardo Castagnoli, Francesca Pala, Poorani Subramanian, Cihan Oguz, Benjamin Schwarz, Ai Ing Lim, Andrew S Burns, Elena Fontana, Marita Bosticardo, Cristina Corsino, Angelina Angelova, Ottavia M Delmonte, Heather Kenney, Deanna Riley, Grace Smith, Lisa Ott de Bruin, Vasileios Oikonomou, Lucas Dos Santos Dias, Danielle Fink, Eric Bohrnsen, Cole D Kimzey, Gian Luigi Marseglia, Guisela Alva-Lozada, Jenna R E Bergerson, Ana Brett, Karlla W Brigatti, Dimana Dimitrova, Cullen M Dutmer, Alexandra F Freeman, Hanadys Ale, Steven M Holland, Francesco Licciardi, Srdjan Pasic, Laura E Poskitt, David E Potts, Joseph F Dasso, Svetlana O Sharapova, Kevin A Strauss, Brant R Ward, Melis Yilmaz, Douglas B Kuhns, Michail S Lionakis, Stephen R Daley, Heidi H Kong, Julia A Segre, Anna Villa, Stefania Pittaluga, Jolan E Walter, Ivan Vujkovic-Cvijin, Yasmine Belkaid, Luigi D Notarangelo","doi":"10.1084/jem.20241993","DOIUrl":"10.1084/jem.20241993","url":null,"abstract":"<p><p>Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12047384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Cardoso, Michael D Buck, Bruno Frederico, Probir Chakravarty, Oliver Schulz, Kok Haw Jonathan Lim, Cécile Piot, Mariana Pereira da Costa, Evangelos Giampazolias, Francesca Gasparrini, Neil Rogers, Caetano Reis E Sousa
{"title":"DNGR-1 regulates proliferation and migration of bone marrow dendritic cell progenitors.","authors":"Ana Cardoso, Michael D Buck, Bruno Frederico, Probir Chakravarty, Oliver Schulz, Kok Haw Jonathan Lim, Cécile Piot, Mariana Pereira da Costa, Evangelos Giampazolias, Francesca Gasparrini, Neil Rogers, Caetano Reis E Sousa","doi":"10.1084/jem.20241813","DOIUrl":"10.1084/jem.20241813","url":null,"abstract":"<p><p>Conventional dendritic cells (cDCs) are sentinel cells that play a crucial role in both innate and adaptive immune responses. cDCs originate from a progenitor (pre-cDC) in the bone marrow (BM) that travels via the blood to seed peripheral tissues before locally differentiating into functional cDC1 and cDC2 cells, as part of a process known as cDCpoiesis. How cDCpoiesis is regulated and whether this affects the output of cDCs is poorly understood. In this study, we show that DNGR-1, an innate immune receptor expressed by cDC progenitors and type 1 cDCs, can regulate cDCpoiesis in mice. In a competitive chimera setting, cDC progenitors lacking DNGR-1 exhibit increased proliferation and tissue migratory potential. Compared with their WT counterparts, DNGR-1-deficient cDC progenitor cells display superior colonization of peripheral tissues but an altered distribution. These findings suggest that cDCpoiesis can be regulated in part by precursor cell-intrinsic processes driven by signals from innate immune receptors such as DNGR-1 that may respond to alterations in the BM milieu.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 8","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12071193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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