Hannah Peckham, Anna Radziszewska, Justyna Sikora, Nina M de Gruijter, Restuadi Restuadi, Melissa Kartawinata, Lucia Martin-Gutierrez, George A Robinson, Claire T Deakin, Lucy R Wedderburn, Elizabeth C Jury, Gary Butler, Emma S Chambers, Elizabeth C Rosser, Coziana Ciurtin
{"title":"Estrogen influences class-switched memory B cell frequency only in humans with two X chromosomes.","authors":"Hannah Peckham, Anna Radziszewska, Justyna Sikora, Nina M de Gruijter, Restuadi Restuadi, Melissa Kartawinata, Lucia Martin-Gutierrez, George A Robinson, Claire T Deakin, Lucy R Wedderburn, Elizabeth C Jury, Gary Butler, Emma S Chambers, Elizabeth C Rosser, Coziana Ciurtin","doi":"10.1084/jem.20241253","DOIUrl":"10.1084/jem.20241253","url":null,"abstract":"<p><p>Sex differences in immunity are well-documented, though mechanisms underpinning these differences remain ill-defined. Here, in a human-only ex vivo study, we demonstrate that postpubertal cisgender females have higher levels of CD19+CD27+IgD- class-switched memory B cells compared with age-matched cisgender males. This increase is only observed after puberty and before menopause, suggesting a strong influence for sex hormones. Accordingly, B cells express high levels of estrogen receptor 2 (ESR2), and class-switch-regulating genes are enriched for ESR2-binding sites. In a gender-diverse cohort, blockade of natal estrogen in transgender males (XX karyotype) reduced class-switched memory B cell frequency, while gender-affirming estradiol treatment in transgender females (XY karyotype) did not increase these levels. In postmenopausal cis-females, class-switched memory B cells were increased in those taking hormone replacement therapy (HRT) compared with those who were not. These data demonstrate that sex hormones and chromosomes work in tandem to impact immune responses, with estrogen only influencing the frequency of class-switched memory B cells in individuals with an XX chromosomal background.</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/PMC11893172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572916","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}
Kerry L Hilligan, Patricia A Darrah, Robert A Seder, Alan Sher
{"title":"Deconvoluting the interplay of innate and adaptive immunity in BCG-induced nonspecific and TB-specific host resistance.","authors":"Kerry L Hilligan, Patricia A Darrah, Robert A Seder, Alan Sher","doi":"10.1084/jem.20240496","DOIUrl":"10.1084/jem.20240496","url":null,"abstract":"<p><p>BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB. Here, we propose that both the mycobacterial-specific and off-target effects of BCG depend on the interplay of adaptive and innate cells and the cytokines they produce, and that the elucidation of this interaction should be a major strategy in the development of more effective BCG-based vaccines and immunotherapies.</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/PMC11917170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657473","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}
Benjamin Israelow, Eric Song, Tianyang Mao, Peiwen Lu, Amit Meir, Feimei Liu, Mia Madel Alfajaro, Jin Wei, Huiping Dong, Robert J Homer, Aaron Ring, Craig B Wilen, Akiko Iwasaki
{"title":"Correction: Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling.","authors":"Benjamin Israelow, Eric Song, Tianyang Mao, Peiwen Lu, Amit Meir, Feimei Liu, Mia Madel Alfajaro, Jin Wei, Huiping Dong, Robert J Homer, Aaron Ring, Craig B Wilen, Akiko Iwasaki","doi":"10.1084/jem.2020124102192025c","DOIUrl":"10.1084/jem.2020124102192025c","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/PMC11864074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143501909","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}
Mi Yang, Qi Guo, Hui Peng, Yu-Zhong Xiao, Ye Xiao, Yan Huang, Chang-Jun Li, Tian Su, Yun-Lin Zhang, Min-Xiang Lei, Hui-Ling Chen, Tie-Jian Jiang, Xiang-Hang Luo
{"title":"Correction: Krüppel-like factor 3 inhibition by mutated lncRNA Reg1cp results in human high bone mass syndrome.","authors":"Mi Yang, Qi Guo, Hui Peng, Yu-Zhong Xiao, Ye Xiao, Yan Huang, Chang-Jun Li, Tian Su, Yun-Lin Zhang, Min-Xiang Lei, Hui-Ling Chen, Tie-Jian Jiang, Xiang-Hang Luo","doi":"10.1084/jem.2018155403172025C","DOIUrl":"10.1084/jem.2018155403172025C","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/PMC11932041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692316","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}
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}
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}
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}
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}
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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
