Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng
{"title":"BCOR and ZC3H12A suppress a core stemness program in exhausted CD8+ T cells.","authors":"Jing Xu, Zeran Jia, Xiaocui Zhao, Lixia Wang, Gang Jin, Zhuoyang Li, Na Yin, Yinqing Li, Min Peng","doi":"10.1084/jem.20241133","DOIUrl":"https://doi.org/10.1084/jem.20241133","url":null,"abstract":"<p><p>In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor-exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of ∼216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.</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/PMC12054362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021147","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}
Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee
{"title":"Gut dysbiosis from high-salt diet promotes glioma via propionate-mediated TGF-β activation.","authors":"Chae Won Kim, Hyun-Jin Kim, In Kang, Keun Bon Ku, Yumin Kim, Jang Hyun Park, Juhee Lim, Byeong Hoon Kang, Won Hyung Park, Jeongwoo La, Sungwoo Chang, Inju Hwang, Minji Kim, Stephen Ahn, Heung Kyu Lee","doi":"10.1084/jem.20241135","DOIUrl":"10.1084/jem.20241135","url":null,"abstract":"<p><p>The purpose of this study is to investigate the impact of a high-salt diet (HSD), which is commonly found in Western countries, on the progression of glioma. Our research shows that the alterations in gut microbiota caused by an HSD facilitated the development of glioma. Mice fed an HSD have elevated levels of intestinal propionate, which accelerated the growth of glioma cells. We also find that propionate supplementation enhanced the response of glioma cells to low oxygen levels. Moreover, we identify a link between TGF-β signaling, response to low oxygen levels, and invasion-related pathways. Propionate treatment increases the expression of HIF-1α, leading to an increase in TGF-β1 production. Additionally, propionate treatment promotes glioma cell invasion through TGF-β signaling. Our findings suggest that an HSD-induced increase in propionate plays a crucial role in glioma progression by facilitating invasion through the hypoxic response and TGF-β signaling pathways, thereby establishing a significant connection between gut microbiota and the progression of glioma.</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/PMC12097148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119809","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}
Michael T Conlon, Jessica Y Huang, Michael Y Gerner
{"title":"Lymphatic chain gradients regulate the magnitude and heterogeneity of T cell responses to vaccination.","authors":"Michael T Conlon, Jessica Y Huang, Michael Y Gerner","doi":"10.1084/jem.20241311","DOIUrl":"https://doi.org/10.1084/jem.20241311","url":null,"abstract":"<p><p>Upon activation, T cells proliferate and differentiate into diverse populations, including highly differentiated effector and memory precursor subsets. Initial diversification is influenced by signals sensed during T cell priming within lymphoid tissues. However, the rules governing how cellular heterogeneity is spatially encoded in vivo remain unclear. Here, we show that immunization establishes concentration gradients of antigens and inflammation across interconnected chains of draining lymph nodes (IC-LNs). While T cells are activated at all sites, individual IC-LNs elicit divergent responses: proximal IC-LNs favor the generation of effector cells, whereas distal IC-LNs promote formation of central memory precursor cells. Although both proximal and distal sites contribute to anamnestic responses, T cells from proximal IC-LNs preferentially provide early effector responses at inflamed tissues. Conversely, T cells from distal IC-LNs demonstrate an enhanced capacity to generate long-lasting responses to chronic antigens in cancer settings, including after checkpoint blockade therapy. Therefore, formation of spatial gradients across lymphatic chains following vaccination regulates the magnitude, heterogeneity, and longevity of T cell responses.</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/PMC12042774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024329","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}
Maryam Vaseghi-Shanjani, Mehul Sharma, Pariya Yousefi, Simran Samra, Kaitlin U Laverty, Arttu Jolma, Rozita Razavi, Ally H W Yang, Mihai Albu, Liam Golding, Anna F Lee, Ryan Tan, Phillip A Richmond, Marita Bosticardo, Jonathan H Rayment, Connie L Yang, Kyla J Hildebrand, Rae Brager, Michelle K Demos, Yu-Lung Lau, Luigi D Notarangelo, Timothy R Hughes, Catherine M Biggs, Stuart E Turvey
{"title":"A multimorphic variant in ThPOK causes an inborn error of immunity with T cell defects and fibrosis.","authors":"Maryam Vaseghi-Shanjani, Mehul Sharma, Pariya Yousefi, Simran Samra, Kaitlin U Laverty, Arttu Jolma, Rozita Razavi, Ally H W Yang, Mihai Albu, Liam Golding, Anna F Lee, Ryan Tan, Phillip A Richmond, Marita Bosticardo, Jonathan H Rayment, Connie L Yang, Kyla J Hildebrand, Rae Brager, Michelle K Demos, Yu-Lung Lau, Luigi D Notarangelo, Timothy R Hughes, Catherine M Biggs, Stuart E Turvey","doi":"10.1084/jem.20241174","DOIUrl":"10.1084/jem.20241174","url":null,"abstract":"<p><p>ThPOK is a transcription factor that acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by a genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2:c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, the transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation and ThPOKK360N-transduced fibroblasts with increased profibrotic gene expression. This novel human disease confirms ThPOK's role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.</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/PMC12091070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110413","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}
Ramona Rica, Monika Waldherr, Emi Miyakoda, Ana Patricia Kutschat, Marlene Schülein, Jing Zhang, Ricardo Alfredo Orbegozo-Medina, Lisa Sandner, Valentina Stolz, Darina Waltenberger, Thomas Krausgruber, Christoph Bock, Nicole Boucheron, Davide Seruggia, Wilfried Ellmeier, Shinya Sakaguchi
{"title":"HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection.","authors":"Ramona Rica, Monika Waldherr, Emi Miyakoda, Ana Patricia Kutschat, Marlene Schülein, Jing Zhang, Ricardo Alfredo Orbegozo-Medina, Lisa Sandner, Valentina Stolz, Darina Waltenberger, Thomas Krausgruber, Christoph Bock, Nicole Boucheron, Davide Seruggia, Wilfried Ellmeier, Shinya Sakaguchi","doi":"10.1084/jem.20240829","DOIUrl":"10.1084/jem.20240829","url":null,"abstract":"<p><p>CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study uncovers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.</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/PMC12135962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215929","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}
Diana Muñoz Sandoval, Florian A Bach, Alasdair Ivens, Adam C Harding, Natasha L Smith, Michalina Mazurczyk, Yrene Themistocleous, Nick J Edwards, Sarah E Silk, Jordan R Barrett, Graeme J M Cowan, Giorgio Napolitani, Nicholas J Savill, Simon J Draper, Angela M Minassian, Wiebke Nahrendorf, Philip J Spence
{"title":"Plasmodium falciparum infection induces T cell tolerance that is associated with decreased disease severity upon re-infection.","authors":"Diana Muñoz Sandoval, Florian A Bach, Alasdair Ivens, Adam C Harding, Natasha L Smith, Michalina Mazurczyk, Yrene Themistocleous, Nick J Edwards, Sarah E Silk, Jordan R Barrett, Graeme J M Cowan, Giorgio Napolitani, Nicholas J Savill, Simon J Draper, Angela M Minassian, Wiebke Nahrendorf, Philip J Spence","doi":"10.1084/jem.20241667","DOIUrl":"https://doi.org/10.1084/jem.20241667","url":null,"abstract":"<p><p>Immunity to severe malaria is acquired quickly, operates independently of pathogen load, and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance remains unknown. We used a human rechallenge model of falciparum malaria in which healthy adult volunteers were infected three times over a 12 mo period to track the development of disease tolerance in real-time. We found that parasitemia triggered a hardwired innate immune response that led to systemic inflammation, pyrexia, and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, a single infection was sufficient to reprogram T cell activation and reduce the number and diversity of effector cells upon rechallenge. Crucially, this did not silence stem-like memory cells but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerized hosts were thus able to prevent collateral tissue damage in the absence of antiparasite immunity.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11987708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023415","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}
Megan K Proulx, Christine D Wiggins, Charlotte J Reames, Claire Wu, Michael C Kiritsy, Ping Xu, Judith C Gallant, Patricia S Grace, Brooke A Fenderson, Clare M Smith, Cecilia S Lindestam Arlehamn, Galit Alter, Douglas A Lauffenburger, Christopher M Sassetti
{"title":"Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans.","authors":"Megan K Proulx, Christine D Wiggins, Charlotte J Reames, Claire Wu, Michael C Kiritsy, Ping Xu, Judith C Gallant, Patricia S Grace, Brooke A Fenderson, Clare M Smith, Cecilia S Lindestam Arlehamn, Galit Alter, Douglas A Lauffenburger, Christopher M Sassetti","doi":"10.1084/jem.20241760","DOIUrl":"10.1084/jem.20241760","url":null,"abstract":"<p><p>While control of Mycobacterium tuberculosis (Mtb) infection is generally understood to require Th1 cells and IFNγ, infection produces a spectrum of immunological and pathological phenotypes in diverse human populations. By characterizing Mtb infection in mouse strains that model the genetic heterogeneity of an outbred population, we identified strains that control Mtb comparably to a standard IFNγ-dependent mouse model but with substantially lower lung IFNγ levels. We report that these mice have a significantly altered CD4 T cell profile that specifically lacks the terminal effector Th1 subset and that this phenotype is detectable before infection. These mice still require T cells to control bacterial burden but are less dependent on IFNγ signaling. Instead, noncanonical immune features such as Th17-like CD4 and γδT cells correlate with low bacterial burden. We find the same Th17 transcriptional programs are associated with resistance to Mtb infection in humans, implicating specific non-Th1 T cell responses as a common feature of Mtb control across species.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795551","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":"Microbiota-centered interventions to boost immune checkpoint blockade therapies.","authors":"Andrew A Almonte, Simon Thomas, Laurence Zitvogel","doi":"10.1084/jem.20250378","DOIUrl":"https://doi.org/10.1084/jem.20250378","url":null,"abstract":"<p><p>Immune checkpoint blockade therapies have markedly advanced cancer treatment by invigorating antitumor immunity and extending patient survival. However, therapeutic resistance and immune-related toxicities remain major concerns. Emerging evidence indicates that microbial dysbiosis diminishes therapeutic response rates, while a diverse gut ecology and key beneficial taxa correlate with improved treatment outcomes. Therefore, there is a growing understanding that manipulating the gut microbiota could boost therapy efficacy. This review examines burgeoning methods that target the gut microbiome to optimize therapy and innovative diagnostic tools to detect dysbiosis, and highlights challenges that remain to be addressed in the field.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005048","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}
Adam J Fike, Kristen N Bricker, Michael V Gonzalez, Anju Maharjan, Tien Bui, Keomonyroth Nuon, Scott M Emrich, Julia L Weber, Sara A Luckenbill, Nicholas M Choi, Renan Sauteraud, Dajiang J Liu, Nancy J Olsen, Roberto Caricchio, Mohamed Trebak, Sathi Babu Chodisetti, Ziaur S M Rahman
{"title":"IRF7 controls spontaneous autoimmune germinal center and plasma cell checkpoints.","authors":"Adam J Fike, Kristen N Bricker, Michael V Gonzalez, Anju Maharjan, Tien Bui, Keomonyroth Nuon, Scott M Emrich, Julia L Weber, Sara A Luckenbill, Nicholas M Choi, Renan Sauteraud, Dajiang J Liu, Nancy J Olsen, Roberto Caricchio, Mohamed Trebak, Sathi Babu Chodisetti, Ziaur S M Rahman","doi":"10.1084/jem.20231882","DOIUrl":"10.1084/jem.20231882","url":null,"abstract":"<p><p>How IRF7 promotes autoimmune B cell responses and systemic autoimmunity is unclear. Analysis of spontaneous SLE-prone mice deficient in IRF7 uncovered the IRF7 role in regulating autoimmune germinal center (GC), plasma cell (PC), and autoantibody responses and disease. IRF7, however, was dispensable for foreign antigen-driven GC, PC, and antibody responses. Competitive bone marrow (BM) chimeras highlighted the importance of IRF7 in hematopoietic cells in spontaneous GC and PC differentiation. Single-cell RNAseq of SLE-prone B cells indicated IRF7-mediated B cell differentiation through GC and PC fates. Mechanistic studies revealed that IRF7 promoted B cell differentiation through GC and PC fates by regulating the transcriptome, translation, and metabolism of SLE-prone B cells. Mixed BM chimeras demonstrated a requirement for B cell-intrinsic IRF7 in IgG autoantibody production but not in the regulation of spontaneous GC and PC responses. Altogether, we delineate previously unknown B cell-intrinsic and -extrinsic mechanisms of IRF7-promoted spontaneous GC and PC responses, loss of tolerance, autoantibody production, and SLE development.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174117","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}
Katrin F Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M Butler, Evi X Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné
{"title":"Factor XII-driven coagulation traps bacterial infections.","authors":"Katrin F Nickel, Anne Jämsä, Sandra Konrath, Praveen Papareddy, Lynn M Butler, Evi X Stavrou, Maike Frye, Mathias Gelderblom, Bernhard Nieswandt, Sven Hammerschmidt, Heiko Herwald, Thomas Renné","doi":"10.1084/jem.20250049","DOIUrl":"https://doi.org/10.1084/jem.20250049","url":null,"abstract":"<p><p>Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)-triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12-/-) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12-/- mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12-/- mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 7","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004769","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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