Juliana J Lee, Liang Yang, Jonathan J Kotzin, Dughan Ahimovic, Michael J Bale, Peter A Nigrovic, Steven Z Josefowicz, Diane Mathis, Christophe Benoist
{"title":"Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks.","authors":"Juliana J Lee, Liang Yang, Jonathan J Kotzin, Dughan Ahimovic, Michael J Bale, Peter A Nigrovic, Steven Z Josefowicz, Diane Mathis, Christophe Benoist","doi":"10.1084/jem.20241207","DOIUrl":"10.1084/jem.20241207","url":null,"abstract":"<p><p>Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052630","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":"Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39.","authors":"Sang-Nee Tan, Jing Hao, Jing Ge, Yazheng Yang, Liguo Liu, Jia Huang, Meng Lin, Xiaohong Zhao, Genyu Wang, Zhiying Yang, Ling Ni, Chen Dong","doi":"10.1084/jem.20240445","DOIUrl":"10.1084/jem.20240445","url":null,"abstract":"<p><p>Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ-expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11797014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189425","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}
Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang P Zhu, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang
{"title":"Correction: Myeloid activation clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer.","authors":"Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang P Zhu, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang","doi":"10.1084/jem.2023196702272025c","DOIUrl":"10.1084/jem.2023196702272025c","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604985","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}
Suin Jo, Ray A Ohara, Derek J Theisen, Sunkyung Kim, Tiantian Liu, Christopher B Bullock, Michelle He, Feiya Ou, Jing Chen, Sytse J Piersma, J Luke Postoak, Wayne M Yokoyama, Michael S Diamond, Theresa L Murphy, Kenneth M Murphy
{"title":"Shared pathway of WDFY4-dependent cross-presentation of immune complexes by cDC1 and cDC2.","authors":"Suin Jo, Ray A Ohara, Derek J Theisen, Sunkyung Kim, Tiantian Liu, Christopher B Bullock, Michelle He, Feiya Ou, Jing Chen, Sytse J Piersma, J Luke Postoak, Wayne M Yokoyama, Michael S Diamond, Theresa L Murphy, Kenneth M Murphy","doi":"10.1084/jem.20240955","DOIUrl":"10.1084/jem.20240955","url":null,"abstract":"<p><p>Priming CD8+ T cells against tumors or viral pathogens results largely from cross-presentation of exogenous antigens by type 1 conventional dendritic cells (cDC1s). Although monocyte-derived DCs and cDC2s can cross-present in vitro, their physiological relevance remains unclear. Here, we used genetic models to evaluate the role of cDC subsets in presentation of cell-associated and immune complex antigens to CD4+ and CD8+ T cells in vivo. For cell-associated antigens, cDC1s were necessary and sufficient to prime both CD4+ and CD8+ T cells. In contrast, for immune complex antigens, either cDC1 or cDC2, but not monocyte-derived DCs, could carry out cross-presentation to CD8+ T cells. Mice lacking cDC1 and vaccinated with immune complexes could cross-prime CD8+ T cells that were sufficient to mediate tumor rejection. Notably, this cross-presentation mediated by cDC2 was also WDFY4 dependent, similar to cross-presentation of cell-associated antigens by cDC1. These results demonstrate a previously unrecognized activity of WDFY4 in cDC2s and suggest a cross-presentation pathway shared by cDC subsets.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364807","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}
Noa Simchoni, Shogo Koide, Maryel Likhite, Yoshihiko Kuchitsu, Senkottuvelan Kadirvel, Christopher S Law, Brett M Elicker, Santosh Kurra, Margaret Mei-Kay Wong, Bo Yuan, Alice Grossi, Ronald M Laxer, Stefano Volpi, Dilan Dissanayake, Tomohiko Taguchi, David B Beck, Tiphanie P Vogel, Anthony K Shum
{"title":"The common HAQ STING allele prevents clinical penetrance of COPA syndrome.","authors":"Noa Simchoni, Shogo Koide, Maryel Likhite, Yoshihiko Kuchitsu, Senkottuvelan Kadirvel, Christopher S Law, Brett M Elicker, Santosh Kurra, Margaret Mei-Kay Wong, Bo Yuan, Alice Grossi, Ronald M Laxer, Stefano Volpi, Dilan Dissanayake, Tomohiko Taguchi, David B Beck, Tiphanie P Vogel, Anthony K Shum","doi":"10.1084/jem.20242179","DOIUrl":"10.1084/jem.20242179","url":null,"abstract":"<p><p>COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% of individuals, with no known mediators of protection. Recent studies implicate STING in the pathogenesis of COPA syndrome. We show that the common HAQ STING allele mediates complete clinical protection. We sequenced 35 individuals with COPA mutations, 26 affected patients and 9 unaffected carriers, finding HAQ STING co-segregation with clinical nonpenetrance. Exome sequencing identified only the mutations comprising HAQ STING as variants shared by unaffected carriers and absent in patients. Experimentally, we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling. Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome. Our study is the first report of a common and well-tolerated allele mediating complete clinical protection from a severe genetic disorder. Our findings redefine the diagnostic criteria for COPA syndrome, expose functional differences among STING alleles with broad scientific and clinical implications, and reveal a potential universal gene therapy approach for patients.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515887","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}
Andrew W Simonson, Joseph J Zeppa, Allison N Bucsan, Michael C Chao, Supriya Pokkali, Forrest Hopkins, Michael R Chase, Andrew J Vickers, Matthew S Sutton, Caylin G Winchell, Amy J Myers, Cassaundra L Ameel, Ryan J Kelly, Ben Krouse, Luke E Hood, Jiaxiang Li, Chelsea C Lehman, Megha Kamath, Jaime Tomko, Mark A Rodgers, Rachel Donlan, Harris Chishti, H Jacob Borish, Edwin Klein, Charles A Scanga, Sarah M Fortune, Philana Ling Lin, Pauline Maiello, Mario Roederer, Patricia A Darrah, Robert A Seder, JoAnne L Flynn
{"title":"Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8α+ lymphocytes.","authors":"Andrew W Simonson, Joseph J Zeppa, Allison N Bucsan, Michael C Chao, Supriya Pokkali, Forrest Hopkins, Michael R Chase, Andrew J Vickers, Matthew S Sutton, Caylin G Winchell, Amy J Myers, Cassaundra L Ameel, Ryan J Kelly, Ben Krouse, Luke E Hood, Jiaxiang Li, Chelsea C Lehman, Megha Kamath, Jaime Tomko, Mark A Rodgers, Rachel Donlan, Harris Chishti, H Jacob Borish, Edwin Klein, Charles A Scanga, Sarah M Fortune, Philana Ling Lin, Pauline Maiello, Mario Roederer, Patricia A Darrah, Robert A Seder, JoAnne L Flynn","doi":"10.1084/jem.20241571","DOIUrl":"10.1084/jem.20241571","url":null,"abstract":"<p><p>Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the BCG route and dose from 5 × 105 CFUs ID to 5 × 107 CFUs i.v. resulted in prevention of Mycobacterium tuberculosis (Mtb) infection and TB disease in highly susceptible nonhuman primates. Identifying immune mechanisms protection following i.v. BCG will facilitate development of more effective vaccines against TB. Here, we depleted lymphocyte subsets prior to and during Mtb challenge in i.v. BCG-vaccinated macaques to identify those necessary for protection. Depletion of adaptive CD4 T cells, but not adaptive CD8αβ T cells, resulted in loss of protection with increased Mtb burdens and dissemination, indicating that CD4 T cells are critical to i.v. BCG-mediated protection. Depletion of unconventional CD8α-expressing lymphocytes (NK cells, innate T cells, and CD4+CD8α+ double-positive T cells) abrogated protection in most i.v. BCG-immunized macaques, supporting further investigation into which of these cell subsets contribute to protection after vaccination.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11801270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255794","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}
Qing Wang, Francesco Boccalatte, Jason Xu, Giovanni Gambi, Bettina Nadorp, Fatema Akter, Carea Mullin, Ashley F Melnick, Elizabeth Choe, Anna C McCarter, Nicole A Jerome, Siyi Chen, Karena Lin, Sarah Khan, Rohan Kodgule, Jonathan H Sussman, Petri Pölönen, Javier Rodriguez-Hernaez, Sonali Narang, Kleopatra Avrampou, Bryan King, Aristotelis Tsirigos, Russell J H Ryan, Charles G Mullighan, David T Teachey, Kai Tan, Iannis Aifantis, Mark Y Chiang
{"title":"Native stem cell transcriptional circuits define cardinal features of high-risk leukemia.","authors":"Qing Wang, Francesco Boccalatte, Jason Xu, Giovanni Gambi, Bettina Nadorp, Fatema Akter, Carea Mullin, Ashley F Melnick, Elizabeth Choe, Anna C McCarter, Nicole A Jerome, Siyi Chen, Karena Lin, Sarah Khan, Rohan Kodgule, Jonathan H Sussman, Petri Pölönen, Javier Rodriguez-Hernaez, Sonali Narang, Kleopatra Avrampou, Bryan King, Aristotelis Tsirigos, Russell J H Ryan, Charles G Mullighan, David T Teachey, Kai Tan, Iannis Aifantis, Mark Y Chiang","doi":"10.1084/jem.20231349","DOIUrl":"10.1084/jem.20231349","url":null,"abstract":"<p><p>While the mutational landscape across early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) and ETP-like leukemia is known, establishing a unified framework that activates stem cell genes characteristic of these tumors remains elusive. Using complementary mouse and human models, chromatin mapping, and enhancer profiling, we show that the coactivator ZMIZ1 promotes normal and malignant ETP population growth by inducing the transcription factor MYB in feedforward circuits to convergently activate oncogenes (MEF2C, MYCN, and BCL2) through essential enhancers. A key superenhancer, the N-Myc regulating enhancer (NMRE), drives malignant ETP population growth but is dispensable for normal lymphopoiesis. This network of stem cell superenhancers identifies treatment-resistant tumors and poor survival outcomes; unifies diverse ETP-ALLs; and contributes to cardinal features of the recently genomically identified high-risk bone marrow progenitor-like (BMP-like) ETP-ALL tumor-stem cell/myeloid gene expression, inhibited NOTCH1-induced T-cell development, aggressive clinical behavior, and venetoclax sensitivity. Since ZMIZ1 is dispensable for essential homeostasis, it might be possible to safely target this network to treat high-risk diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 4","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449232","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}
Zhe Chen, Feng Wu, Yan Li, Lei Li, Yufei Lei, Siwei Gao, Tao Chen, Yuxin Xie, Jianwen Xiao, Hanqing Zeng, Jianchuan Deng, Xueya Zhao, Yu Hou
{"title":"Inhibition of DEK restores hematopoietic stem cell function in Fanconi anemia.","authors":"Zhe Chen, Feng Wu, Yan Li, Lei Li, Yufei Lei, Siwei Gao, Tao Chen, Yuxin Xie, Jianwen Xiao, Hanqing Zeng, Jianchuan Deng, Xueya Zhao, Yu Hou","doi":"10.1084/jem.20241248","DOIUrl":"10.1084/jem.20241248","url":null,"abstract":"<p><p>Hematopoietic stem cells (HSCs) are susceptible to replication stress, which is a major contributor to HSC defects in Fanconi anemia (FA). Here, we report that HSCs relax the global chromatin by downregulating the expression of a chromatin architectural protein, DEK, in response to replication stress. DEK is abnormally accumulated in bone marrow (BM) CD34+ cells from patients with FA and in Fancd2-deficient HSCs. DEK haploinsufficiency promotes chromatin relaxation, replication stress relief, and function recovery of Fancd2-deficient HSCs. Furthermore, inhibition of DEK restores the proliferation of FA CD34+ cells in vitro and enhances their engraftment in vivo. Mechanistically, the activating transcription factor 2 (ATF2), specifically phosphorylated ATF2 at Thr69/71, was identified as a promoter of DEK transcription. Fancd2 deficiency results in p38 hyperphosphorylation, which in turn phosphorylates ATF2 at Thr69/71, leading to DEK accumulation in HSCs. In conclusion, our findings establish a functional link between chromatin relaxation and replication stress tolerance in HSCs and highlight DEK as a target for FA.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 3","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059203","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}
Shan Miao, Hao Li, Xiaohan Song, Yongbo Liu, Gaoyang Wang, Chen Kan, Youqiong Ye, Ru-Juan Liu, Hua-Bing Li
{"title":"tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells.","authors":"Shan Miao, Hao Li, Xiaohan Song, Yongbo Liu, Gaoyang Wang, Chen Kan, Youqiong Ye, Ru-Juan Liu, Hua-Bing Li","doi":"10.1084/jem.20240559","DOIUrl":"10.1084/jem.20240559","url":null,"abstract":"<p><p>Activation of CD8+ T cells necessitates rapid metabolic reprogramming to fulfill the substantial biosynthetic demands of effector functions. However, the posttranscriptional mechanisms underpinning this process remain obscure. The transfer RNA (tRNA) N1-methyladenine (m1A) modification, essential for tRNA stability and protein translation, has an undefined physiological function in CD8+ T cells, particularly in antitumor responses. Here, we demonstrate that the tRNA m1A \"writer\" gene Trmt61a enhances the tumor-killing capacity of CD8+ T cells by regulating cholesterol biosynthesis. Deletion of Trmt61a in CD8+ T cells leads to a compromised tumor-killing function in both in vivo and in vitro assays. Mechanistically, tRNA m1A promotes antitumor immunity in CD8+ T cells by enhancing the translation of ATP citrate lyase, a key enzyme for cholesterol biosynthesis. Cholesterol supplementation rescues the impaired tumor-killing function and proliferation of TRMT61A-deficient CD8+ T cells. Our findings highlight tRNA m1A modification as a regulatory checkpoint in cholesterol metabolism in CD8+ T cells, suggesting potential novel strategies for cancer immunotherapy.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 3","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059297","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}
Carlos Gomez-Diaz, Wilhelm Greulich, Benedikt Wefers, Meiyue Wang, Silvia Bolsega, Maike Effern, Daniel P Varga, Zhe Han, Minyi Chen, Marleen Bérouti, Natascia Leonardi, Ulrike Schillinger, Bernhard Holzmann, Arthur Liesz, Axel Roers, Michael Hölzel, Marijana Basic, Wolfgang Wurst, Veit Hornung
{"title":"RNase T2 restricts TLR13-mediated autoinflammation in vivo.","authors":"Carlos Gomez-Diaz, Wilhelm Greulich, Benedikt Wefers, Meiyue Wang, Silvia Bolsega, Maike Effern, Daniel P Varga, Zhe Han, Minyi Chen, Marleen Bérouti, Natascia Leonardi, Ulrike Schillinger, Bernhard Holzmann, Arthur Liesz, Axel Roers, Michael Hölzel, Marijana Basic, Wolfgang Wurst, Veit Hornung","doi":"10.1084/jem.20241424","DOIUrl":"10.1084/jem.20241424","url":null,"abstract":"<p><p>RNA-sensing TLRs are strategically positioned in the endolysosome to detect incoming nonself RNA. RNase T2 plays a critical role in processing long, structured RNA into short oligoribonucleotides that engage TLR7 or TLR8. In addition to its positive regulatory role, RNase T2 also restricts RNA recognition through unknown mechanisms, as patients deficient in RNase T2 suffer from neuroinflammation. Consistent with this, mice lacking RNase T2 exhibit interferon-dependent neuroinflammation, impaired hematopoiesis, and splenomegaly. However, the mechanism by which RNase T2 deficiency unleashes inflammation in vivo remains unknown. Here, we report that the inflammatory phenotype found in Rnaset2-/- mice is completely reversed in the absence of TLR13, suggesting aberrant accumulation of an RNA ligand for this receptor. Interestingly, this TLR13-driven inflammatory phenotype is also fully present in germ-free mice, suggesting a role for RNase T2 in limiting erroneous TLR13 activation by an as yet unidentified endogenous ligand. These results establish TLR13 as a potential self-sensor that is kept in check by RNase T2.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 3","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032941","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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