Jorden I Lane, Elida Nieves-Ortiz, Ornella Ndatabaye, Aliia R Fatkhullina, Sebastian Lopez, Terence S Dermody, Daria Esterházy
{"title":"Intestinal lymphatic vasculature is functionally adapted to different drainage regions and is altered by helminth infection.","authors":"Jorden I Lane, Elida Nieves-Ortiz, Ornella Ndatabaye, Aliia R Fatkhullina, Sebastian Lopez, Terence S Dermody, Daria Esterházy","doi":"10.1084/jem.20241181","DOIUrl":"10.1084/jem.20241181","url":null,"abstract":"<p><p>We sought to determine whether the lymphatic vasculature functionally adapts to the organ in which it resides, such as along the gut. Duodenal lymphatic capillaries (lacteals) displayed the most discontinuous tight junction composition within the gut, resulting in a dependence on duodenal lacteals for rapid dietary lipid uptake. Duodenal helminths abrogated these features. Parallel RNA sequencing of lymphatic endothelial cells and mucosa along the intestine revealed that the transcriptomes overlapped in functional profiles. RNA sequencing also identified a putative VEGFR-2/3 signaling gradient that may explain differences in lacteal tight junctions along the small intestine at homeostasis. Transcriptionally, helminth infection triggered antimicrobial and angiogenic responses. While microbial depletion acted additively to helminths on lymphatic restructuring, glucocorticoids partially reversed helminth-induced lacteal changes. This suggests helminths induce lymphangiogenesis and associated lymphatic \"zippering\" via inflammation. Our study uncovers and explains the superior lipid absorption by duodenal lacteals and how it is compromised by helminths and provides transcriptional insights into lymphatic function along the gut.</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/PMC12162095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284907","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}
Riem Gawish, Rajagopal Varada, Florian Deckert, Anastasiya Hladik, Linda Steinbichl, Laura Cimatti, Katarina Milanovic, Mamta Jain, Natalya Torgasheva, Andrea Tanzer, Kim De Paepe, Tom Van de Wiele, Bela Hausmann, Michaela Lang, Martin Pechhacker, Nahla Ibrahim, Ingrid De Vries, Christine Brostjan, Michael Sixt, Christoph Gasche, Louis Boon, David Berry, Michael F Jantsch, Fatima C Pereira, Cornelia Vesely
{"title":"Filamin A editing in myeloid cells reduces intestinal inflammation and protects from colitis.","authors":"Riem Gawish, Rajagopal Varada, Florian Deckert, Anastasiya Hladik, Linda Steinbichl, Laura Cimatti, Katarina Milanovic, Mamta Jain, Natalya Torgasheva, Andrea Tanzer, Kim De Paepe, Tom Van de Wiele, Bela Hausmann, Michaela Lang, Martin Pechhacker, Nahla Ibrahim, Ingrid De Vries, Christine Brostjan, Michael Sixt, Christoph Gasche, Louis Boon, David Berry, Michael F Jantsch, Fatima C Pereira, Cornelia Vesely","doi":"10.1084/jem.20240109","DOIUrl":"10.1084/jem.20240109","url":null,"abstract":"<p><p>Patho-mechanistic origins of ulcerative colitis are still poorly understood. The actin cross-linker filamin A (FLNA) impacts cellular responses through interaction with cytosolic proteins. Posttranscriptional A-to-I editing generates two forms of FLNA: genome-encoded FLNAQ and FLNAR. FLNA is edited in colon fibroblasts, smooth muscle cells, and endothelial cells. We found that the FLNA editing status determines colitis severity. Editing was highest in healthy colons and reduced during murine and human colitis. Mice that exclusively express FLNAR were highly resistant to DSS-induced colitis, whereas fully FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced transcriptional states of structural cells and microbiome composition, we found that FLNAR exerts protection specifically via myeloid cells, which are physiologically unedited. Introducing fixed FLNAR did not hamper cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. Thus, loss of FLNA editing correlates with colitis severity, and targeted editing of myeloid cells serves as a novel therapeutic approach in intestinal inflammation.</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/PMC12139521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225670","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}
Kun Peng, Xiaoxue Zhao, Hongjian Li, Yang-Xin Fu, Yong Liang
{"title":"Membrane-IL12 adjuvant mRNA vaccine polarizes pre-effector T cells for optimized tumor control.","authors":"Kun Peng, Xiaoxue Zhao, Hongjian Li, Yang-Xin Fu, Yong Liang","doi":"10.1084/jem.20241454","DOIUrl":"https://doi.org/10.1084/jem.20241454","url":null,"abstract":"<p><p>Conventional mRNA cancer vaccines can expand the quantity of tumor-specific CD8 T cells, but their effector function might be compromised. Specific cytokine signaling may enhance T cell differentiation for better tumor killing. We screened various cytokines and identified IL-12 as a potent adjuvant for mRNA vaccines, though with significant systemic toxicity. To balance efficacy and toxicity, we developed a membrane-tethered IL-12 (mtIL12) adjuvant mRNA vaccine. This design restricts mtIL12 expression to the surface of antigen-presenting cells, thereby selectively activating antigen-specific T cells without affecting bystander T or NK cells. mtIL12 adjuvant mRNA vaccination induced a unique pre-effector T cell subset that gives rise to highly responsive effector T cells, resulting in superior anti-tumor activity. Moreover, this approach overcame immune checkpoint therapy resistance and prevented cancer metastasis. Our study highlights that next-generation mRNA vaccines encoding membrane-tethered cytokine adjuvants can generate potent effector T cells, offering effective tumor control with reduced toxicity.</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/PMC12143231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248195","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}
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}
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":"https://doi.org/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}
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":"https://doi.org/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}
{"title":"\"What's in a name?\" Clarifying the identity of RORγt+ antigen-presenting cells.","authors":"Feiya Ou, Kenneth M Murphy","doi":"10.1084/jem.20250760","DOIUrl":"https://doi.org/10.1084/jem.20250760","url":null,"abstract":"<p><p>Recent publications have demonstrated that antigen-presenting cells (APCs) targeted by Rorc-cre (also known as RORγt-cre) are required for the induction of peripheral regulatory T (pTreg) cells in response to commensal and dietary antigens. In this issue of JEM, Sun et al. (https://doi.org/10.1084/jem.20250573) provide key insights into the identity of these cells, revealing that Rorc-cre-traced APCs include group 3 innate lymphoid cells (ILC3s), dendritic cells (DCs), and extrathymic AIRE-expressing cells (eTACs). Their work highlights eTACs as critical for inducing RORγt+ pTregs specific to food antigens, while implicating DCs in the generation of RORγt- pTregs.</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/PMC12080405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078303","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}
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