{"title":"The partitioning of TCR repertoires by thymic selection.","authors":"Wan-Lin Lo, Eric S Huseby","doi":"10.1084/jem.20230897","DOIUrl":"10.1084/jem.20230897","url":null,"abstract":"<p><p>αβ T cells are critical components of the adaptive immune system; they maintain tissue and immune homeostasis during health, provide sterilizing immunity after pathogen infection, and are capable of eliminating transformed tumor cells. Fundamental to these distinct functions is the ligand specificity of the unique antigen receptor expressed on each mature T cell (TCR), which endows lymphocytes with the ability to behave in a cell-autonomous, disease context-specific manner. Clone-specific behavioral properties are initially established during T cell development when thymocytes use TCR recognition of major histocompatibility complex (MHC) and MHC-like ligands to instruct survival versus death and to differentiate into a plethora of inflammatory and regulatory T cell lineages. Here, we review the ligand specificity of the preselection thymocyte repertoire and argue that developmental stage-specific alterations in TCR signaling control cross-reactivity and foreign versus self-specificity of T cell sublineages.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017683","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}
Boyoung Shin, Samantha J Chang, Brendan W MacNabb, Ellen V Rothenberg
{"title":"Transcriptional network dynamics in early T cell development.","authors":"Boyoung Shin, Samantha J Chang, Brendan W MacNabb, Ellen V Rothenberg","doi":"10.1084/jem.20230893","DOIUrl":"10.1084/jem.20230893","url":null,"abstract":"<p><p>The rate at which cells enter the T cell pathway depends not only on the immigration of hematopoietic precursors into the strong Notch signaling environment of the thymus but also on the kinetics with which each individual precursor cell reaches T-lineage commitment once it arrives. Notch triggers a complex, multistep gene regulatory network in the cells in which the steps are stereotyped but the transition speeds between steps are variable. Progenitor-associated transcription factors delay T-lineage differentiation even while Notch-induced transcription factors within the same cells push differentiation forward. Progress depends on regulator cross-repression, on breaching chromatin barriers, and on shifting, competitive collaborations between stage-specific and stably expressed transcription factors, as reviewed here.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017684","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":"A path forward for Staphylococcus aureus vaccine development.","authors":"Stephanie A Fritz, Juliane Bubeck Wardenburg","doi":"10.1084/jem.20240002","DOIUrl":"10.1084/jem.20240002","url":null,"abstract":"<p><p>The pursuit of a vaccine to quell Staphylococcus aureus disease has been unfruitful. In this Viewpoint, we explore the biological linkage between microbial niche acquisition and host immunity as a basis to guide future vaccine efforts.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988051","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":"Adjusting to self in the thymus: CD4 versus CD8 lineage commitment and regulatory T cell development.","authors":"Isabel Baldwin, Ellen A Robey","doi":"10.1084/jem.20230896","DOIUrl":"10.1084/jem.20230896","url":null,"abstract":"<p><p>During thymic development, thymocytes adjust their TCR response based on the strength of their reactivity to self-peptide MHC complexes. This tuning process allows thymocytes with a range of self-reactivities to survive positive selection and contribute to a diverse T cell pool. In this review, we will discuss recent advances in our understanding of how thymocytes tune their responsiveness during positive selection, and we present a \"sequential selection\" model to explain how MHC specificity influences lineage choice. We also discuss recent evidence for cell type diversity in the medulla and discuss how this heterogeneity may contribute to medullary niches for negative selection and regulatory T cell development.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558878","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":"Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance.","authors":"Naijun Miao, Dongqing Cao, Jingsi Jin, Guizhi Ma, Haihui Yu, Junwen Qu, Guiping Li, Caixia Gao, Dong Dong, Fan Xia, Wenwen Li","doi":"10.1084/jem.20231486","DOIUrl":"10.1084/jem.20231486","url":null,"abstract":"<p><p>Changes in mechanosensitive ion channels following radiation have seldom been linked to therapeutic sensitivity or specific factors involved in antitumor immunity. Here, in this study, we found that the mechanical force sensor, Piezo2, was significantly upregulated in tumor cells after radiation, and Piezo2 knockout in tumor cells enhanced tumor growth suppression by radiotherapy. Specifically, loss of Piezo2 in tumor cells induced their IL-15 expression via unleashing JAK2/STAT1/IRF-1 axis after radiation. This increase in IL-15 activates IL-15Rα on tumor-infiltrating CD8+ T cells, thereby leading to their augmented effector and stem cell-like properties, along with reduced terminal exhausted feature. Importantly, Piezo2 expression was negatively correlated with CD8 infiltration, as well as with radiosensitivity of patients with rectum adenocarcinoma receiving radiotherapy treatment. Together, our findings reveal that tumor cell-intrinsic Piezo2 induces radioresistance by dampening the IRF-1/IL-15 axis, thus leading to impaired CD8+ T cell-dependent antitumor responses, providing insights into the further development of combination strategies to treat radioresistant cancers.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017685","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":"Iron TAMs: The fallen protectors.","authors":"Lijuan Sun, Mikala Egeblad","doi":"10.1084/jem.20240951","DOIUrl":"10.1084/jem.20240951","url":null,"abstract":"<p><p>A new study by Folkert et al. (https://doi.org/10.1084/jem.20230420) defines an \"iron-rich\" subset of tumor-associated macrophages (iTAMs). The metabolism of heme leads to the degradation of the transcriptional repressor Bach1 and shapes the transcriptional profile of iTAMs. The endothelin receptor B in iTAMs signals tumor-supportive functions.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11441312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347954","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}
Ana Portelinha, Shenqiu Wang, Sara Parsa, Man Jiang, Alexander N Gorelick, Sagarajit Mohanty, Soumya Sharma, Elisa de Stanchina, Marjan Berishaj, Chunying Zhao, James Heward, Neeraj K Aryal, Omid Tavana, Jiayu Wen, Jude Fitzgibbon, Ahmet Dogan, Anas Younes, Ari M Melnick, Hans-Guido Wendel
{"title":"SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.","authors":"Ana Portelinha, Shenqiu Wang, Sara Parsa, Man Jiang, Alexander N Gorelick, Sagarajit Mohanty, Soumya Sharma, Elisa de Stanchina, Marjan Berishaj, Chunying Zhao, James Heward, Neeraj K Aryal, Omid Tavana, Jiayu Wen, Jude Fitzgibbon, Ahmet Dogan, Anas Younes, Ari M Melnick, Hans-Guido Wendel","doi":"10.1084/jem.20231143","DOIUrl":"10.1084/jem.20231143","url":null,"abstract":"<p><p>The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132924","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}
Raphaël Jeger-Madiot, Delphine Planas, Isabelle Staropoli, Hippolyte Debarnot, Jérôme Kervevan, Héloïse Mary, Camilla Collina, Barbara F Fonseca, Rémy Robinot, Stacy Gellenoncourt, Olivier Schwartz, Lorna Ewart, Michael Bscheider, Samy Gobaa, Lisa A Chakrabarti
{"title":"Modeling memory B cell responses in a lymphoid organ-chip to evaluate mRNA vaccine boosting.","authors":"Raphaël Jeger-Madiot, Delphine Planas, Isabelle Staropoli, Hippolyte Debarnot, Jérôme Kervevan, Héloïse Mary, Camilla Collina, Barbara F Fonseca, Rémy Robinot, Stacy Gellenoncourt, Olivier Schwartz, Lorna Ewart, Michael Bscheider, Samy Gobaa, Lisa A Chakrabarti","doi":"10.1084/jem.20240289","DOIUrl":"10.1084/jem.20240289","url":null,"abstract":"<p><p>Predicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a lymphoid organ-chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 spike protein mimicked a vaccine boost by inducing a massive amplification of spike-specific memory B cells, plasmablast differentiation, and spike-specific antibody secretion. Features of lymphoid tissue, including the formation of activated CD4+ T cell/B cell clusters and the emigration of matured plasmablasts, were recapitulated in the LO chip. Importantly, myeloid cells were competent at capturing and expressing mRNA vectored by lipid nanoparticles, enabling the assessment of responses to mRNA vaccines. Comparison of on-chip responses to Wuhan monovalent and Wuhan/Omicron bivalent mRNA vaccine boosts showed equivalent induction of Omicron neutralizing antibodies, pointing at immune imprinting as reported in vivo. The LO chip thus represents a versatile platform suited to the preclinical evaluation of vaccine-boosting strategies.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140214","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}
Adrian Gervais, Astrid Marchal, Andrea Fortova, Michaela Berankova, Lenka Krbkova, Martina Pychova, Jiri Salat, Shuxiang Zhao, Nacim Kerrouche, Tom Le Voyer, Karin Stiasny, Simon Raffl, Anne Schieber Pachart, Samira Fafi-Kremer, Simon Gravier, Davide F Robbiani, Laurent Abel, Margaret R MacDonald, Charles M Rice, Gaia Weissmann, Tarek Kamal Eldin, Eva Robatscher, Elke Maria Erne, Elisabetta Pagani, Alessandro Borghesi, Anne Puel, Paul Bastard, Aurélie Velay, Martin Martinot, Yves Hansmann, Judith H Aberle, Daniel Ruzek, Aurélie Cobat, Shen-Ying Zhang, Jean-Laurent Casanova
{"title":"Autoantibodies neutralizing type I IFNs underlie severe tick-borne encephalitis in ∼10% of patients.","authors":"Adrian Gervais, Astrid Marchal, Andrea Fortova, Michaela Berankova, Lenka Krbkova, Martina Pychova, Jiri Salat, Shuxiang Zhao, Nacim Kerrouche, Tom Le Voyer, Karin Stiasny, Simon Raffl, Anne Schieber Pachart, Samira Fafi-Kremer, Simon Gravier, Davide F Robbiani, Laurent Abel, Margaret R MacDonald, Charles M Rice, Gaia Weissmann, Tarek Kamal Eldin, Eva Robatscher, Elke Maria Erne, Elisabetta Pagani, Alessandro Borghesi, Anne Puel, Paul Bastard, Aurélie Velay, Martin Martinot, Yves Hansmann, Judith H Aberle, Daniel Ruzek, Aurélie Cobat, Shen-Ying Zhang, Jean-Laurent Casanova","doi":"10.1084/jem.20240637","DOIUrl":"10.1084/jem.20240637","url":null,"abstract":"<p><p>Tick-borne encephalitis (TBE) virus (TBEV) is transmitted to humans via tick bites. Infection is benign in >90% of the cases but can cause mild (<5%), moderate (<4%), or severe (<1%) encephalitis. We show here that ∼10% of patients hospitalized for severe TBE in cohorts from Austria, Czech Republic, and France carry auto-Abs neutralizing IFN-α2, -β, and/or -ω at the onset of disease, contrasting with only ∼1% of patients with moderate and mild TBE. These auto-Abs were found in two of eight patients who died and none of 13 with silent infection. The odds ratios (OR) for severe TBE in individuals with these auto-Abs relative to those without them in the general population were 4.9 (95% CI: 1.5-15.9, P < 0.0001) for the neutralization of only 100 pg/ml IFN-α2 and/or -ω, and 20.8 (95% CI: 4.5-97.4, P < 0.0001) for the neutralization of 10 ng/ml IFN-α2 and -ω. Auto-Abs neutralizing type I IFNs accounted for ∼10% of severe TBE cases in these three European cohorts.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307869","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}
Nikolaos Angelis, Anna Baulies, Florian Hubl, Anna Kucharska, Gavin Kelly, Miriam Llorian, Stefan Boeing, Vivian S W Li
{"title":"Loss of ARID3A perturbs intestinal epithelial proliferation-differentiation ratio and regeneration.","authors":"Nikolaos Angelis, Anna Baulies, Florian Hubl, Anna Kucharska, Gavin Kelly, Miriam Llorian, Stefan Boeing, Vivian S W Li","doi":"10.1084/jem.20232279","DOIUrl":"10.1084/jem.20232279","url":null,"abstract":"<p><p>Intestinal stem cells at the crypt divide and give rise to progenitor cells that proliferate and differentiate into various mature cell types in the transit-amplifying (TA) zone. Here, we showed that the transcription factor ARID3A regulates intestinal epithelial cell proliferation and differentiation at the TA progenitors. ARID3A forms an expression gradient from the villus tip to the upper crypt mediated by TGF-β and WNT. Intestinal-specific deletion of Arid3a reduces crypt proliferation, predominantly in TA cells. Bulk and single-cell transcriptomic analysis shows increased enterocyte and reduced secretory differentiation in the Arid3a cKO intestine, accompanied by enriched upper-villus gene signatures of both cell lineages. We find that the enhanced epithelial differentiation in the Arid3a-deficient intestine is caused by increased binding and transcription of HNF1 and HNF4. Finally, we show that loss of Arid3a impairs irradiation-induced regeneration with sustained cell death and reprogramming. Our findings imply that Arid3a functions to fine-tune the proliferation-differentiation dynamics at the TA progenitors, which are essential for injury-induced regeneration.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988052","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}