Pub Date : 2025-11-13DOI: 10.1016/j.immuni.2025.10.020
Jennifer M. Umhoefer, Maya M. Arce, Sivakanthan Kasinathan, Sean Whalen, Rama Dajani, Sanjana Subramanya, Laine Goudy, Julia A. Belk, Royce Zhou, Minh T.N. Pham, Wenxi Zhang, Rosmely Hernandez, Carinna Tran, Nikhita Kirthivasan, Jacob W. Freimer, Cody T. Mowery, Vinh Nguyen, Mineto Ota, Benjamin G. Gowen, Dimitre R. Simeonov, Alexander Marson
FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Treg cells). Although mice exclusively express FOXP3 in Treg cells, stimulated conventional CD4+ T cells (Tconv cells) also transiently express FOXP3 in humans. Mechanisms governing these distinct expression patterns need elucidation. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Treg and Tconv cells to identify cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv cell FOXP3 expression depended on a subset of Treg cell CREs, as well as Tconv-cell-selective positive (NS+) and negative (NS−) CREs. Combinatorial silencing of Tconv cell CREs revealed their epistatic logic. These CREs are occupied and regulated by TFs that we identified as FOXP3 regulators. Finally, mutagenesis of murine NS− CRE revealed its essentiality for restricting FOXP3 expression to Treg cells. We map CRE and TF circuitry to reveal distinct cell- and species-specific regulation of FOXP3 expression.
{"title":"FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry","authors":"Jennifer M. Umhoefer, Maya M. Arce, Sivakanthan Kasinathan, Sean Whalen, Rama Dajani, Sanjana Subramanya, Laine Goudy, Julia A. Belk, Royce Zhou, Minh T.N. Pham, Wenxi Zhang, Rosmely Hernandez, Carinna Tran, Nikhita Kirthivasan, Jacob W. Freimer, Cody T. Mowery, Vinh Nguyen, Mineto Ota, Benjamin G. Gowen, Dimitre R. Simeonov, Alexander Marson","doi":"10.1016/j.immuni.2025.10.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.020","url":null,"abstract":"FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Treg cells). Although mice exclusively express FOXP3 in Treg cells, stimulated conventional CD4<sup>+</sup> T cells (Tconv cells) also transiently express FOXP3 in humans. Mechanisms governing these distinct expression patterns need elucidation. Here, we performed CRISPR screens tiling the <em>FOXP3</em> locus and targeting TFs in human Treg and Tconv cells to identify <em>cis</em>-regulatory elements (CREs) and <em>trans</em>-regulators of FOXP3. Tconv cell FOXP3 expression depended on a subset of Treg cell CREs, as well as Tconv-cell-selective positive (NS+) and negative (NS−) CREs. Combinatorial silencing of Tconv cell CREs revealed their epistatic logic. These CREs are occupied and regulated by TFs that we identified as FOXP3 regulators. Finally, mutagenesis of murine NS− CRE revealed its essentiality for restricting FOXP3 expression to Treg cells. We map CRE and TF circuitry to reveal distinct cell- and species-specific regulation of FOXP3 expression.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"19 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-13DOI: 10.1016/j.immuni.2025.11.010
Min Woo Kim, Jonathan Kipnis
(Immunity 58, 1040–1051; May 13, 2025)
（豁免58,1040-1051；2025年5月13日）
{"title":"Glymphatics and meningeal lymphatics unlock the brain-immune code","authors":"Min Woo Kim, Jonathan Kipnis","doi":"10.1016/j.immuni.2025.11.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.11.010","url":null,"abstract":"(Immunity <em>58</em>, 1040–1051; May 13, 2025)","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"21 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.019
Christoph A. Thaiss, Ye Tian, Daniel A. Winer, Michelle Linterman, Adrian Liston, Corina Amor, Scott W. Lowe, Guang-Hui Liu
Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve not only longevity but also health span.
{"title":"Aging and immunity","authors":"Christoph A. Thaiss, Ye Tian, Daniel A. Winer, Michelle Linterman, Adrian Liston, Corina Amor, Scott W. Lowe, Guang-Hui Liu","doi":"10.1016/j.immuni.2025.10.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.019","url":null,"abstract":"Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve not only longevity but also health span.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"252 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.016
Vassilis Glaros, Taras Kreslavsky
Until recently, the existence of long-lived IgE-secreting plasma cells was debated. Using timestamping in mouse models of type 2 inflammation, two studies in this issue of Immunity reveal the long-term persistence of IgE-secreting plasma cells in secondary lymphoid organs rather than in the bone marrow.
{"title":"Hidden survivors: Long-lived IgE-secreting plasma cells in the spleen","authors":"Vassilis Glaros, Taras Kreslavsky","doi":"10.1016/j.immuni.2025.10.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.016","url":null,"abstract":"Until recently, the existence of long-lived IgE-secreting plasma cells was debated. Using timestamping in mouse models of type 2 inflammation, two studies in this issue of <em>Immunity</em> reveal the long-term persistence of IgE-secreting plasma cells in secondary lymphoid organs rather than in the bone marrow.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"164 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.015
Zheng Jin, Bo Zhu
Immunosuppressive monocyte-derived macrophages are key targets in cancer therapy; however, the mechanisms of their replenishment and functional plasticity remain elusive. In a recent issue of Nature, Hedge et al. challenge the conventional view that immunosuppressive macrophages are acquired exclusively through tumor microenvironment reprogramming; instead, their study demonstrates that the developmental fate of these macrophages is predisposed in the bone marrow.
{"title":"Tame the Hydra’s head: Targeting bone marrow maladaptive myelopoiesis to reverse macrophage-mediated immunosuppression in cancer","authors":"Zheng Jin, Bo Zhu","doi":"10.1016/j.immuni.2025.10.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.015","url":null,"abstract":"Immunosuppressive monocyte-derived macrophages are key targets in cancer therapy; however, the mechanisms of their replenishment and functional plasticity remain elusive. In a recent issue of <em>Nature</em>, Hedge et al. challenge the conventional view that immunosuppressive macrophages are acquired exclusively through tumor microenvironment reprogramming; instead, their study demonstrates that the developmental fate of these macrophages is predisposed in the bone marrow.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.018
Hocheol Shin, Joon Seok Park
Gut microbial metabolites modulate immune responses to tumors. In this issue of Immunity, Bachem et al.1 demonstrate that microbiota-derived butyrate cooperates with the transcription factor Foxo1 to promote CD8+ T cell stemness and enhance responsiveness to immune checkpoint inhibitors in melanoma.
{"title":"Fermenting T cell stemness for cancer immunity","authors":"Hocheol Shin, Joon Seok Park","doi":"10.1016/j.immuni.2025.10.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.018","url":null,"abstract":"Gut microbial metabolites modulate immune responses to tumors. In this issue of <em>Immunity</em>, Bachem et al.<span><span><sup>1</sup></span></span> demonstrate that microbiota-derived butyrate cooperates with the transcription factor Foxo1 to promote CD8<sup>+</sup> T cell stemness and enhance responsiveness to immune checkpoint inhibitors in melanoma.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"105 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11Epub Date: 2025-10-21DOI: 10.1016/j.immuni.2025.09.018
Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller
Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically "cold" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.
{"title":"Spatial immune profiling defines a subset of human gliomas with functional tertiary lymphoid structures.","authors":"Pinar Cakmak, Jennifer H Lun, Aakanksha Singh, Jadranka Macas, Jonathan Schupp, Jonas Schuck, Zeina Mahmoud, Miriam Köhler, Tatjana Starzetz, Michael C Burger, Eike Steidl, Lucie Marie Hasse, Elke Hattingen, Karl H Plate, Yvonne Reiss, Katharina Imkeller","doi":"10.1016/j.immuni.2025.09.018","DOIUrl":"10.1016/j.immuni.2025.09.018","url":null,"abstract":"<p><p>Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically \"cold\" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2847-2863.e8"},"PeriodicalIF":26.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.010
Maria Backhaus, Kai Markus Schneider
Sympathetic signaling has been implicated in colitis, but the precise circuits remain unclear. In this issue of Immunity, Sharma et al. demonstrate that myeloid cell-specific loss of DNA-demethylation dampens sympathetic signaling-driven colitis exacerbation in an IL-1β-dependent manner.
{"title":"Myeloid TET2 tips the balance of neuro-epithelial crosstalk","authors":"Maria Backhaus, Kai Markus Schneider","doi":"10.1016/j.immuni.2025.10.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.010","url":null,"abstract":"Sympathetic signaling has been implicated in colitis, but the precise circuits remain unclear. In this issue of <em>Immunity</em>, Sharma et al. demonstrate that myeloid cell-specific loss of DNA-demethylation dampens sympathetic signaling-driven colitis exacerbation in an IL-1β-dependent manner.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"39 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.immuni.2025.10.017
Justine Fiefvet, Lidia Yshii
Regulatory T cells can play conflicting roles in autoimmune inflammation. In this issue of Immunity, Benamar et al. reveal that gut-microbiota-induced Notch3+ regulatory T cells migrate to the central nervous system in multiple sclerosis and transition to inflammatory Th17-like cells.
{"title":"A Notch too far: Treg plasticity in multiple sclerosis","authors":"Justine Fiefvet, Lidia Yshii","doi":"10.1016/j.immuni.2025.10.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.017","url":null,"abstract":"Regulatory T cells can play conflicting roles in autoimmune inflammation. In this issue of <em>Immunity</em>, Benamar et al. reveal that gut-microbiota-induced Notch3<sup>+</sup> regulatory T cells migrate to the central nervous system in multiple sclerosis and transition to inflammatory Th17-like cells.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"1 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-07DOI: 10.1016/j.immuni.2025.10.008
Ester Marina-Zárate, Henry J. Sutton, Paul G. Lopez, Tasha K. Altheide, Michael Bick, Iszac Burton, Elana Ben-Akiva, Katarzyna Kaczmarek Michaels, Kesha Hyacinth, Brandon S. Healy, Deuk Lim, Lars Hangartner, Dennis R. Burton, Diane G. Carnathan, Guido Silvestri, William R. Schief, Darrell J. Irvine, Shane Crotty
Durability of T follicular helper (Tfh) cell responses is pivotal for generating high affinity antibodies. We characterized Tfh cell responses to HIV Env immunization longitudinally in non-human primates, analyzing >500,000 CD4+ T cells from 192 lymph node (LN) samples collected over 60 weeks, including >36,000 vaccine-specific Tfh cells. An escalating-dose priming regimen elicited higher and more sustained Tfh cell responses in LNs, compared with conventional bolus immunization. Multiple vaccine-specific germinal center (GC)-Tfh subpopulations, including interleukin (IL)4hi and IL21hi GC-Tfh cells, were continually present. Antigen-specific Tfh clones persisted within GCs for over 6 months, maintaining stable gene expression profiles and showing no signs of exhaustion. Vaccine-specific Tfh proliferation signatures were detectable for 27+ weeks after priming. Tfh subpopulations correlated with HIV Env-specific antibody and neutralization titers. Additionally, substantial Tfh clonal migration occurred between LNs. Thus, complex populations of GC-Tfh can enhance antibody responses and survive for 48 weeks in GC responses without new antigen delivery, with implications for immunization regimens.
{"title":"Highly functional and prolonged germinal center T follicular helper cell responses are associated with enhanced neutralizing antibody development","authors":"Ester Marina-Zárate, Henry J. Sutton, Paul G. Lopez, Tasha K. Altheide, Michael Bick, Iszac Burton, Elana Ben-Akiva, Katarzyna Kaczmarek Michaels, Kesha Hyacinth, Brandon S. Healy, Deuk Lim, Lars Hangartner, Dennis R. Burton, Diane G. Carnathan, Guido Silvestri, William R. Schief, Darrell J. Irvine, Shane Crotty","doi":"10.1016/j.immuni.2025.10.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.10.008","url":null,"abstract":"Durability of T follicular helper (Tfh) cell responses is pivotal for generating high affinity antibodies. We characterized Tfh cell responses to HIV Env immunization longitudinally in non-human primates, analyzing >500,000 CD4<sup>+</sup> T cells from 192 lymph node (LN) samples collected over 60 weeks, including >36,000 vaccine-specific Tfh cells. An escalating-dose priming regimen elicited higher and more sustained Tfh cell responses in LNs, compared with conventional bolus immunization. Multiple vaccine-specific germinal center (GC)-Tfh subpopulations, including interleukin (IL)4<sup>hi</sup> and IL21<sup>hi</sup> GC-Tfh cells, were continually present. Antigen-specific Tfh clones persisted within GCs for over 6 months, maintaining stable gene expression profiles and showing no signs of exhaustion. Vaccine-specific Tfh proliferation signatures were detectable for 27+ weeks after priming. Tfh subpopulations correlated with HIV Env-specific antibody and neutralization titers. Additionally, substantial Tfh clonal migration occurred between LNs. Thus, complex populations of GC-Tfh can enhance antibody responses and survive for 48 weeks in GC responses without new antigen delivery, with implications for immunization regimens.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"39 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145454664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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