Francesca Pala, Luigi D Notarangelo, Marita Bosticardo
{"title":"Rediscovering the human thymus through cutting-edge technologies.","authors":"Francesca Pala, Luigi D Notarangelo, Marita Bosticardo","doi":"10.1084/jem.20230892","DOIUrl":"10.1084/jem.20230892","url":null,"abstract":"<p><p>Recent technological advances have transformed our understanding of the human thymus. Innovations such as high-resolution imaging, single-cell omics, and organoid cultures, including thymic epithelial cell (TEC) differentiation and culture, and improvements in biomaterials, have further elucidated the thymus architecture, cellular dynamics, and molecular mechanisms underlying T cell development, and have unraveled previously unrecognized levels of stromal cell heterogeneity. These advancements offer unprecedented insights into thymic biology and hold promise for the development of novel therapeutic strategies for immune-related disorders.</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/PMC11338284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017640","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}
Graham Anderson, Emilie J Cosway, Kieran D James, Izumi Ohigashi, Yousuke Takahama
{"title":"Generation and repair of thymic epithelial cells.","authors":"Graham Anderson, Emilie J Cosway, Kieran D James, Izumi Ohigashi, Yousuke Takahama","doi":"10.1084/jem.20230894","DOIUrl":"10.1084/jem.20230894","url":null,"abstract":"<p><p>In the vertebrate immune system, thymus stromal microenvironments support the generation of αβT cells from immature thymocytes. Thymic epithelial cells are of particular importance, and the generation of cortical and medullary epithelial lineages from progenitor stages controls the initiation and maintenance of thymus function. Here, we discuss the developmental pathways that regulate thymic epithelial cell diversity during both the embryonic and postnatal periods. We also examine how thymus microenvironments respond to injury, with particular focus on mechanisms that ensure regeneration of thymic epithelial cells for the restoration of thymus function.</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/PMC11232892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558879","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}
Deeksha Deep, Herman Gudjonson, Chrysothemis C Brown, Samuel A Rose, Roshan Sharma, Yoselin A Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R Wesemann, Virginia Pascual, Dana Pe'er, Alexander Y Rudensky
{"title":"Precursor central memory versus effector cell fate and naïve CD4+ T cell heterogeneity.","authors":"Deeksha Deep, Herman Gudjonson, Chrysothemis C Brown, Samuel A Rose, Roshan Sharma, Yoselin A Paucar Iza, Seunghee Hong, Saskia Hemmers, Michail Schizas, Zhong-Min Wang, Yuezhou Chen, Duane R Wesemann, Virginia Pascual, Dana Pe'er, Alexander Y Rudensky","doi":"10.1084/jem.20231193","DOIUrl":"https://doi.org/10.1084/jem.20231193","url":null,"abstract":"<p><p>Upon antigenic stimulation, naïve CD4+ T cells can give rise to phenotypically distinct effector T helper cells and long-lived memory T cells. We computationally reconstructed the in vivo trajectory of CD4+ T cell differentiation during a type I inflammatory immune response and identified two distinct differentiation paths for effector and precursor central memory T cells arising directly from naïve CD4+ T cells. Unexpectedly, our studies revealed heterogeneity among naïve CD4+ T cells, which are typically considered homogeneous save for their diverse T cell receptor usage. Specifically, a previously unappreciated population of naïve CD4+ T cells sensing environmental type I IFN exhibited distinct activation thresholds, suggesting that naïve CD4+ T cell differentiation potential may be influenced by environmental cues. This population was expanded in human viral infection and type I IFN response-lined autoimmunity. Understanding the relevance of naïve T cell heterogeneity to beneficial and maladaptive T cell responses may have therapeutic implications for adoptive T cell therapies in cancer immunotherapy and vaccination.</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":"142347955","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}
Anne Doye, Paul Chaintreuil, Chantal Lagresle-Peyrou, Ludovic Batistic, Valentine Marion, Patrick Munro, Celine Loubatier, Rayana Chirara, Nataël Sorel, Boris Bessot, Pauline Bronnec, Julie Contenti, Johan Courjon, Valerie Giordanengo, Arnaud Jacquel, Pascal Barbry, Marie Couralet, Nathalie Aladjidi, Alain Fischer, Marina Cavazzana, Coralie Mallebranche, Orane Visvikis, Sven Kracker, Despina Moshous, Els Verhoeyen, Laurent Boyer
{"title":"RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation.","authors":"Anne Doye, Paul Chaintreuil, Chantal Lagresle-Peyrou, Ludovic Batistic, Valentine Marion, Patrick Munro, Celine Loubatier, Rayana Chirara, Nataël Sorel, Boris Bessot, Pauline Bronnec, Julie Contenti, Johan Courjon, Valerie Giordanengo, Arnaud Jacquel, Pascal Barbry, Marie Couralet, Nathalie Aladjidi, Alain Fischer, Marina Cavazzana, Coralie Mallebranche, Orane Visvikis, Sven Kracker, Despina Moshous, Els Verhoeyen, Laurent Boyer","doi":"10.1084/jem.20231562","DOIUrl":"10.1084/jem.20231562","url":null,"abstract":"<p><p>A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.</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/PMC11363864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108002","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}
Ian W Folkert, William A Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J Lazar, Khalida Wani, William P Israel, Zhan Zhang, Venkata S Chaluvadi, Robert J Norgard, Ying Liu, Ashley M Fuller, Mai T Dang, Robert E Roses, Giorgos C Karakousis, John T Miura, Douglas L Fraker, T S Karin Eisinger-Mathason, M Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar
{"title":"An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis.","authors":"Ian W Folkert, William A Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J Lazar, Khalida Wani, William P Israel, Zhan Zhang, Venkata S Chaluvadi, Robert J Norgard, Ying Liu, Ashley M Fuller, Mai T Dang, Robert E Roses, Giorgos C Karakousis, John T Miura, Douglas L Fraker, T S Karin Eisinger-Mathason, M Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar","doi":"10.1084/jem.20230420","DOIUrl":"https://doi.org/10.1084/jem.20230420","url":null,"abstract":"<p><p>We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location-perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic 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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347953","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}
William O Hahn, K Rachael Parks, Mingchao Shen, Gabriel Ozorowski, Holly Janes, Lamar Ballweber-Fleming, Amanda S Woodward Davis, Chris Duplessis, Mark Tomai, Antu K Dey, Zachary K Sagawa, Stephen C De Rosa, Aaron Seese, Latha Kallur Siddaramaiah, Leonidas Stamatatos, Wen-Hsin Lee, Leigh M Sewall, Dalton Karlinsey, Hannah L Turner, Vanessa Rubin, Sarah Furth, Kellie MacPhee, Michael Duff, Lawrence Corey, Michael C Keefer, Srilatha Edupuganti, Ian Frank, Janine Maenza, Lindsey R Baden, Ollivier Hyrien, Rogier W Sanders, John P Moore, Andrew B Ward, Georgia D Tomaras, David C Montefiori, Nadine Rouphael, M Juliana McElrath
{"title":"Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies.","authors":"William O Hahn, K Rachael Parks, Mingchao Shen, Gabriel Ozorowski, Holly Janes, Lamar Ballweber-Fleming, Amanda S Woodward Davis, Chris Duplessis, Mark Tomai, Antu K Dey, Zachary K Sagawa, Stephen C De Rosa, Aaron Seese, Latha Kallur Siddaramaiah, Leonidas Stamatatos, Wen-Hsin Lee, Leigh M Sewall, Dalton Karlinsey, Hannah L Turner, Vanessa Rubin, Sarah Furth, Kellie MacPhee, Michael Duff, Lawrence Corey, Michael C Keefer, Srilatha Edupuganti, Ian Frank, Janine Maenza, Lindsey R Baden, Ollivier Hyrien, Rogier W Sanders, John P Moore, Andrew B Ward, Georgia D Tomaras, David C Montefiori, Nadine Rouphael, M Juliana McElrath","doi":"10.1084/jem.20240604","DOIUrl":"10.1084/jem.20240604","url":null,"abstract":"<p><p>Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.</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/PMC11380150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132925","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":"Judy Lieberman: Stay curious and excited about science.","authors":"Montserrat Cols","doi":"10.1084/jem.20241556","DOIUrl":"https://doi.org/10.1084/jem.20241556","url":null,"abstract":"Judy Lieberman is a professor of pediatrics and adjunct professor of genetics at Harvard Medical School and an endowed chair in cellular and molecular medicine. Her lab studies cytotoxic T lymphocytes (CTL), key cells in the immune defense against viral infection and cancer, as well as molecular pathways activated by the granzymes, and how RNA interference (RNAi) regulates cell differentiation in health and disease states. We spoke to Judy about advice for early career researchers, how she first become interested in cytotoxic T lymphocytes, and key people who have provided mentorship across her career.","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268578","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}
{"title":"PTPN2 deficiency: Amping up JAK/STAT.","authors":"Joshua M Tobin, Megan A Cooper","doi":"10.1084/jem.20240980","DOIUrl":"10.1084/jem.20240980","url":null,"abstract":"<p><p>Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727261","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}
Yi-Hao Chan, Vanja Lundberg, Jérémie Le Pen, Jiayi Yuan, Danyel Lee, Francesca Pinci, Stefano Volpi, Koji Nakajima, Vincent Bondet, Sanna Åkesson, Noopur V Khobrekar, Aaron Bodansky, Likun Du, Tina Melander, Alice-Andrée Mariaggi, Yoann Seeleuthner, Tariq Shikh Saleh, Debanjana Chakravarty, Per Marits, Kerry Dobbs, Sofie Vonlanthen, Viktoria Hennings, Karolina Thörn, Darawan Rinchai, Lucy Bizien, Matthieu Chaldebas, Ali Sobh, Tayfun Özçelik, Sevgi Keles, Suzan A AlKhater, Carolina Prando, Isabelle Meyts, Michael R Wilson, Jérémie Rosain, Emmanuelle Jouanguy, Mélodie Aubart, Laurent Abel, Trine H Mogensen, Qiang Pan-Hammarström, Daxing Gao, Darragh Duffy, Aurélie Cobat, Stefan Berg, Luigi D Notarangelo, Oliver Harschnitz, Charles M Rice, Lorenz Studer, Jean-Laurent Casanova, Olov Ekwall, Shen-Ying Zhang
{"title":"SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.","authors":"Yi-Hao Chan, Vanja Lundberg, Jérémie Le Pen, Jiayi Yuan, Danyel Lee, Francesca Pinci, Stefano Volpi, Koji Nakajima, Vincent Bondet, Sanna Åkesson, Noopur V Khobrekar, Aaron Bodansky, Likun Du, Tina Melander, Alice-Andrée Mariaggi, Yoann Seeleuthner, Tariq Shikh Saleh, Debanjana Chakravarty, Per Marits, Kerry Dobbs, Sofie Vonlanthen, Viktoria Hennings, Karolina Thörn, Darawan Rinchai, Lucy Bizien, Matthieu Chaldebas, Ali Sobh, Tayfun Özçelik, Sevgi Keles, Suzan A AlKhater, Carolina Prando, Isabelle Meyts, Michael R Wilson, Jérémie Rosain, Emmanuelle Jouanguy, Mélodie Aubart, Laurent Abel, Trine H Mogensen, Qiang Pan-Hammarström, Daxing Gao, Darragh Duffy, Aurélie Cobat, Stefan Berg, Luigi D Notarangelo, Oliver Harschnitz, Charles M Rice, Lorenz Studer, Jean-Laurent Casanova, Olov Ekwall, Shen-Ying Zhang","doi":"10.1084/jem.20231725","DOIUrl":"10.1084/jem.20231725","url":null,"abstract":"<p><p>Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11256911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633619","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}
Irem Kaymak, McLane J Watson, Brandon M Oswald, Shixin Ma, Benjamin K Johnson, Lisa M DeCamp, Batsirai M Mabvakure, Katarzyna M Luda, Eric H Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M Kitchen-Goosen, Alexandra Vander Ark, Michael S Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P Roddy, Gillian A Kingsbury, Cristovão M Sousa, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Susan M Kaech, Dominic G Roy, Russell G Jones
{"title":"ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.","authors":"Irem Kaymak, McLane J Watson, Brandon M Oswald, Shixin Ma, Benjamin K Johnson, Lisa M DeCamp, Batsirai M Mabvakure, Katarzyna M Luda, Eric H Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M Kitchen-Goosen, Alexandra Vander Ark, Michael S Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P Roddy, Gillian A Kingsbury, Cristovão M Sousa, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Susan M Kaech, Dominic G Roy, Russell G Jones","doi":"10.1084/jem.20231820","DOIUrl":"10.1084/jem.20231820","url":null,"abstract":"<p><p>Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988050","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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