Regulatory T cells (Treg cells) represent a primary barrier to the development of effective antitumor immunity. Here, we report that reprogramming Treg cells by shifting the expression of FOXP3 from its full-length isoform (FOXP3FL) to a short isoform with exon 2 skipped (FOXP3dE2) promotes CD8 T cell–mediated antitumor immunity. FOXP3dE2 mRNA expression in triple-negative breast cancer tissue positively correlated with overall patient survival. Mice expressing only the FOXP3dE2 isoform were resistant to the development of multiple types of tumors. Tumor-infiltrating Treg cells expressing the FOXP3dE2 isoform exhibited lower immunosuppressive activity and promoted CD8 T cell activation. In addition, we designed a morpholino oligo to induce FOXP3 exon 2 skipping, which similarly enhanced antitumor activity in mouse tumor models and the killing capacity of autologous tumor-infiltrating T cells against patient-derived tumor organoids. Our results suggest that promoting FOXP3dE2 expression reprograms Treg cells to T helper–like cells, thereby enhancing antitumor immunity.
{"title":"Reprogramming intratumoral Treg cells by morpholino-mediated splicing of FOXP3 for cancer immunotherapy","authors":"Yujing Li, Naresh Singh, Chuanpeng Dong, Samantha Sharma, Zhuolong Zhou, Jianguang Du, Maya Haouili, Yile Jiao, Emily Hopewell, Yunlong Liu, Mateusz Opyrchal, Xinna Zhang, Baohua Zhou, Xiongbin Lu","doi":"10.1126/sciimmunol.adr9933","DOIUrl":"10.1126/sciimmunol.adr9933","url":null,"abstract":"<div >Regulatory T cells (T<sub>reg</sub> cells) represent a primary barrier to the development of effective antitumor immunity. Here, we report that reprogramming T<sub>reg</sub> cells by shifting the expression of FOXP3 from its full-length isoform (FOXP3<sup>FL</sup>) to a short isoform with exon 2 skipped (FOXP3<sup>dE2</sup>) promotes CD8 T cell–mediated antitumor immunity. <i>FOXP3<sup>dE2</sup></i> mRNA expression in triple-negative breast cancer tissue positively correlated with overall patient survival. Mice expressing only the FOXP3<sup>dE2</sup> isoform were resistant to the development of multiple types of tumors. Tumor-infiltrating T<sub>reg</sub> cells expressing the FOXP3<sup>dE2</sup> isoform exhibited lower immunosuppressive activity and promoted CD8 T cell activation. In addition, we designed a morpholino oligo to induce FOXP3 exon 2 skipping, which similarly enhanced antitumor activity in mouse tumor models and the killing capacity of autologous tumor-infiltrating T cells against patient-derived tumor organoids. Our results suggest that promoting FOXP3<sup>dE2</sup> expression reprograms T<sub>reg</sub> cells to T helper–like cells, thereby enhancing antitumor immunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891813","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 : 2025-08-15DOI: 10.1126/sciimmunol.adr6787
Ruth Fair-Mäkelä, Pinja Thorén, Joni Näsiaho, Pia Sundqvist, Irina Piiroinen, Laura Kähäri, Ilkka Julkunen, Johanna Ivaska, Elin Hub, Antal Rot, Bishwa Ghimire, Jonna Alanko, Marko Salmi
Lymph node (LN) stromal cells are critical regulators of immune reactions, yet their responses to different SARS-CoV-2 vaccines remain unexplored. Here, we immunized mice with clinically approved gene- and protein-based COVID-19 vaccines targeting viral spike (S) protein and analyzed the draining LN stroma using multimodal bioimaging, single-cell transcriptomics, and functional studies. We found that messenger RNA and adenovirus vector vaccines transfected lymphatic endothelial cell and fibroblastic reticular cell subsets in vivo and led to early local S protein production in the draining LN in a vaccine-specific manner. The vaccines induced rapid transcriptomic reprogramming of the LN stromal cells, which functionally altered scavenging and parenchymal transfer of lymph-borne antigens, formation of chemokine gradients, and migration of eosinophils within LNs. Thus, distinct vaccine formulations targeting S protein differentially prime the draining LN stromal cells before the arrival of migratory dendritic cells bearing immunogens.
{"title":"COVID-19 vaccine type controls stromal reprogramming in draining lymph nodes","authors":"Ruth Fair-Mäkelä, Pinja Thorén, Joni Näsiaho, Pia Sundqvist, Irina Piiroinen, Laura Kähäri, Ilkka Julkunen, Johanna Ivaska, Elin Hub, Antal Rot, Bishwa Ghimire, Jonna Alanko, Marko Salmi","doi":"10.1126/sciimmunol.adr6787","DOIUrl":"10.1126/sciimmunol.adr6787","url":null,"abstract":"<div >Lymph node (LN) stromal cells are critical regulators of immune reactions, yet their responses to different SARS-CoV-2 vaccines remain unexplored. Here, we immunized mice with clinically approved gene- and protein-based COVID-19 vaccines targeting viral spike (S) protein and analyzed the draining LN stroma using multimodal bioimaging, single-cell transcriptomics, and functional studies. We found that messenger RNA and adenovirus vector vaccines transfected lymphatic endothelial cell and fibroblastic reticular cell subsets in vivo and led to early local S protein production in the draining LN in a vaccine-specific manner. The vaccines induced rapid transcriptomic reprogramming of the LN stromal cells, which functionally altered scavenging and parenchymal transfer of lymph-borne antigens, formation of chemokine gradients, and migration of eosinophils within LNs. Thus, distinct vaccine formulations targeting S protein differentially prime the draining LN stromal cells before the arrival of migratory dendritic cells bearing immunogens.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adr6787","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853889","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}
Pub Date : 2025-08-15DOI: 10.1126/sciimmunol.adp3978
Graham D. Hogg, Alyssa G. Weinstein, Natalie L. Kingston, Xiuting Liu, Olivia M. Dres, Liang-I Kang, Varintra E. Lander, Yu-Lan Kao, Faiz Ahmad, Brett L. Knolhoff, Varun V. Shenoy, Blake Sells, Reyka G. Jayasinghe, Andrew Houston, Tiantian Liu, John M. Herndon, Kenneth M. Murphy, Li Ding, Ryan C. Fields, Roheena Z. Panni, William G. Hawkins, David G. DeNardo
T cell–directed immunotherapies have largely failed to slow progression of pancreatic ductal adenocarcinoma (PDAC) because of poor tumor antigenicity and an immunosuppressive tumor microenvironment. We hypothesized that conventional dendritic cell (cDC) suppression in PDAC may further impair tumor immunity. We found that low tissue expression of Fms-like tyrosine kinase 3 ligand (Flt3L) partially underlies cDC deficits. Treatment with systemic Flt3L and CD40 agonists restored cDC number and function in murine models and clinical trial samples from patients with PDAC. CD40 agonism alone did not fully activate cDCs; however, when combined with Flt3L, dual therapy triggered a cDC-driven type I immune response characterized by T cell infiltration, interleukin-12 production, and reciprocal interferon-γ (IFN-γ) responses. In mice, cDC1s were responsible for CD8+ T cell expansion, and in turn, T cell–derived IFN-γ enhanced cDC1 survival. Nevertheless, Flt3L and CD40 agonism increased regulatory T cells through the activation of cDC2s, dampening immunity. These findings advocate further exploration of DC-centered approaches to enhance antitumor immunity in PDAC.
{"title":"Combined Flt3L and CD40 agonism restores dendritic cell–driven T cell immunity in pancreatic cancer","authors":"Graham D. Hogg, Alyssa G. Weinstein, Natalie L. Kingston, Xiuting Liu, Olivia M. Dres, Liang-I Kang, Varintra E. Lander, Yu-Lan Kao, Faiz Ahmad, Brett L. Knolhoff, Varun V. Shenoy, Blake Sells, Reyka G. Jayasinghe, Andrew Houston, Tiantian Liu, John M. Herndon, Kenneth M. Murphy, Li Ding, Ryan C. Fields, Roheena Z. Panni, William G. Hawkins, David G. DeNardo","doi":"10.1126/sciimmunol.adp3978","DOIUrl":"10.1126/sciimmunol.adp3978","url":null,"abstract":"<div >T cell–directed immunotherapies have largely failed to slow progression of pancreatic ductal adenocarcinoma (PDAC) because of poor tumor antigenicity and an immunosuppressive tumor microenvironment. We hypothesized that conventional dendritic cell (cDC) suppression in PDAC may further impair tumor immunity. We found that low tissue expression of Fms-like tyrosine kinase 3 ligand (Flt3L) partially underlies cDC deficits. Treatment with systemic Flt3L and CD40 agonists restored cDC number and function in murine models and clinical trial samples from patients with PDAC. CD40 agonism alone did not fully activate cDCs; however, when combined with Flt3L, dual therapy triggered a cDC-driven type I immune response characterized by T cell infiltration, interleukin-12 production, and reciprocal interferon-γ (IFN-γ) responses. In mice, cDC1s were responsible for CD8<sup>+</sup> T cell expansion, and in turn, T cell–derived IFN-γ enhanced cDC1 survival. Nevertheless, Flt3L and CD40 agonism increased regulatory T cells through the activation of cDC2s, dampening immunity. These findings advocate further exploration of DC-centered approaches to enhance antitumor immunity in PDAC.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp3978","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853893","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}
Peripheral helper T (TPH) cells can play pathogenic roles in human autoimmune diseases. TPH cells are proposed to be the major B cell helpers in inflamed joints in rheumatoid arthritis (RA), but whether and how TPH cells are engaged in tissue inflammation remains unclear. We demonstrate that TPH cells comprise two subsets in RA: stem-like TPH (S-TPH) and effector TPH (E-TPH) cells. These two subsets differed in transcriptome, epigenome, B cell helper capacity, spatial localization, and cell interactions. S-TPH cells displayed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) in synovial tissue together with B cells. S-TPH cells potently induced B cells to produce immunoglobulins. By contrast, E-TPH cells expressed effector molecules and colocalized with proinflammatory macrophages and CD8+ T cells outside TLSs. S-TPH cells could differentiate into E-TPH cells upon TCR stimulation and coculture with B cells. Collectively, our study shows that S-TPH cells play a central role in promoting TPH responses by undergoing self-renewal and seeding E-TPH cells.
{"title":"Stem-like and effector peripheral helper T cells comprise distinct subsets in rheumatoid arthritis","authors":"Yuki Masuo, Akinori Murakami, Rinko Akamine, Osamu Iri, Shunsuke Uno, Koichi Murata, Kohei Nishitani, Hiromu Ito, Ryu Watanabe, Takayuki Fujii, Takeshi Iwasaki, Shinichiro Nakamura, Shinichi Kuriyama, Yugo Morita, Yasuhiro Murakawa, Chikashi Terao, Yukinori Okada, Motomu Hashimoto, Shuichi Matsuda, Hideki Ueno, Hiroyuki Yoshitomi","doi":"10.1126/sciimmunol.adt3955","DOIUrl":"10.1126/sciimmunol.adt3955","url":null,"abstract":"<div >Peripheral helper T (T<sub>PH</sub>) cells can play pathogenic roles in human autoimmune diseases. T<sub>PH</sub> cells are proposed to be the major B cell helpers in inflamed joints in rheumatoid arthritis (RA), but whether and how T<sub>PH</sub> cells are engaged in tissue inflammation remains unclear. We demonstrate that T<sub>PH</sub> cells comprise two subsets in RA: stem-like T<sub>PH</sub> (S-T<sub>PH</sub>) and effector T<sub>PH</sub> (E-T<sub>PH</sub>) cells. These two subsets differed in transcriptome, epigenome, B cell helper capacity, spatial localization, and cell interactions. S-T<sub>PH</sub> cells displayed self-renewal capacity and were mainly found within tertiary lymphoid structures (TLSs) in synovial tissue together with B cells. S-T<sub>PH</sub> cells potently induced B cells to produce immunoglobulins. By contrast, E-T<sub>PH</sub> cells expressed effector molecules and colocalized with proinflammatory macrophages and CD8<sup>+</sup> T cells outside TLSs. S-T<sub>PH</sub> cells could differentiate into E-T<sub>PH</sub> cells upon TCR stimulation and coculture with B cells. Collectively, our study shows that S-T<sub>PH</sub> cells play a central role in promoting T<sub>PH</sub> responses by undergoing self-renewal and seeding E-T<sub>PH</sub> cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853877","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 : 2025-08-08DOI: 10.1126/sciimmunol.adq2055
Mengjie Hu,Dong Pan,Meng Jiao,Xuhui Bao,Xinjian Liu,Fang Li,Chuan-Yuan Li
Budding uninhibited by benzimidazoles 1 (BUB1) is a nuclear serine/threonine protein kinase that ensures proper chromosome segregation before mitosis. We report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and the ensuing immune response. Tumors deficient in BUB1 were sensitive to radiotherapy in a CD8 T cell-dependent manner. We found increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS dsRNA-sensing pathway. Mechanistically, we found that after radiation exposure, BUB1 underwent nucleus-to-cytoplasm migration, where it bound and phosphorylated the poly(A)-binding protein PABPC1, which was degraded together with its associated messenger RNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response.
{"title":"A noncanonical cytoplasmic role for BUB1 in restraining DNA damage-induced dsRNA accumulation and sensing within stress granules.","authors":"Mengjie Hu,Dong Pan,Meng Jiao,Xuhui Bao,Xinjian Liu,Fang Li,Chuan-Yuan Li","doi":"10.1126/sciimmunol.adq2055","DOIUrl":"https://doi.org/10.1126/sciimmunol.adq2055","url":null,"abstract":"Budding uninhibited by benzimidazoles 1 (BUB1) is a nuclear serine/threonine protein kinase that ensures proper chromosome segregation before mitosis. We report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and the ensuing immune response. Tumors deficient in BUB1 were sensitive to radiotherapy in a CD8 T cell-dependent manner. We found increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS dsRNA-sensing pathway. Mechanistically, we found that after radiation exposure, BUB1 underwent nucleus-to-cytoplasm migration, where it bound and phosphorylated the poly(A)-binding protein PABPC1, which was degraded together with its associated messenger RNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"44 1","pages":"eadq2055"},"PeriodicalIF":24.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802544","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 : 2025-08-08DOI: 10.1126/sciimmunol.aea6150
{"title":"Erratum for the Research Article \"Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening\" by L. U. B. Enk et al.","authors":"","doi":"10.1126/sciimmunol.aea6150","DOIUrl":"https://doi.org/10.1126/sciimmunol.aea6150","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"16 1","pages":"eaea6150"},"PeriodicalIF":24.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802580","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 : 2025-08-08DOI: 10.1126/sciimmunol.adt0688
Julia Gschwend,Antonie Lechner,Nikolaos D Sidiropoulos,Paul Maier,Tilde Andersson,Flurin Sturzenegger,Basak Corak,Nina Brander,David A Bejarano,Elina Wells,Sandra P Melo,Joana R D Martins,Maximilian Nitschké,Ari B Molofsky,Andreas Schlitzer,Isabelle C Arnold,Sarah Mundt,Burkhard Becher,Manfred Kopf,Hubert Rehrauer,Christoph Schneider
Pulmonary conventional dendritic cells (cDCs) are functionally and phenotypically heterogeneous antigen-presenting cells essential for orchestrating adaptive immune responses in the lung. Here, we define a cell-intrinsic role for granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in the development of a CD301b+ subset of terminally differentiated cDC2s, in addition to CD103+XCR1+ cDC1s. Unbiased single-cell transcriptomic profiling of CD11c+ cells identified both immature and differentiated lung cDC populations. GM-CSF deficiency disrupted antiapoptotic Bcl2a1 up-regulation and impaired progression to the CD301b+ transcriptional state. Despite the positioning of CD301b+ cDC2s in lymphoid cell-rich adventitial cuff areas, hematopoietic GM-CSF was dispensable for their development. Instead, alveolar epithelial type 2 cell-derived GM-CSF was required for CD301b+ cDC2 formation and pulmonary type 2 immune responses, highlighting the central role of GM-CSF signaling in shaping the pulmonary myeloid landscape.
{"title":"GM-CSF derived from alveolar type 2 cells promotes CD301b+ cDC2 generation and allergic airway inflammation.","authors":"Julia Gschwend,Antonie Lechner,Nikolaos D Sidiropoulos,Paul Maier,Tilde Andersson,Flurin Sturzenegger,Basak Corak,Nina Brander,David A Bejarano,Elina Wells,Sandra P Melo,Joana R D Martins,Maximilian Nitschké,Ari B Molofsky,Andreas Schlitzer,Isabelle C Arnold,Sarah Mundt,Burkhard Becher,Manfred Kopf,Hubert Rehrauer,Christoph Schneider","doi":"10.1126/sciimmunol.adt0688","DOIUrl":"https://doi.org/10.1126/sciimmunol.adt0688","url":null,"abstract":"Pulmonary conventional dendritic cells (cDCs) are functionally and phenotypically heterogeneous antigen-presenting cells essential for orchestrating adaptive immune responses in the lung. Here, we define a cell-intrinsic role for granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in the development of a CD301b+ subset of terminally differentiated cDC2s, in addition to CD103+XCR1+ cDC1s. Unbiased single-cell transcriptomic profiling of CD11c+ cells identified both immature and differentiated lung cDC populations. GM-CSF deficiency disrupted antiapoptotic Bcl2a1 up-regulation and impaired progression to the CD301b+ transcriptional state. Despite the positioning of CD301b+ cDC2s in lymphoid cell-rich adventitial cuff areas, hematopoietic GM-CSF was dispensable for their development. Instead, alveolar epithelial type 2 cell-derived GM-CSF was required for CD301b+ cDC2 formation and pulmonary type 2 immune responses, highlighting the central role of GM-CSF signaling in shaping the pulmonary myeloid landscape.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"14 1","pages":"eadt0688"},"PeriodicalIF":24.8,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144802541","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 : 2025-08-01DOI: 10.1126/sciimmunol.aea8733
Robin R. Kobylski, Laura A. Solt
A gene signature predicts infection severity and all-cause mortality across risk factors modifiable with lifestyle changes and treatment.
一种基因标记可以预测感染的严重程度和全因死亡率，这些风险因素可以随着生活方式的改变和治疗而改变。
{"title":"Immune signature clues are key to unlocking the mystery of clinical responses","authors":"Robin R. Kobylski, Laura A. Solt","doi":"10.1126/sciimmunol.aea8733","DOIUrl":"10.1126/sciimmunol.aea8733","url":null,"abstract":"<div >A gene signature predicts infection severity and all-cause mortality across risk factors modifiable with lifestyle changes and treatment.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758671","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 : 2025-08-01DOI: 10.1126/sciimmunol.adv0985
Manuel M. Gómez de las Heras, Elisa Carrasco, Mario Pérez-Manrique, Naohiro Inohara, Sandra Delgado-Pulido, Álvaro Fernández-Almeida, María I. Gálvez-Castaño, Isaac Francos-Quijorna, Carolina Simó, Virginia García-Cañas, José Ignacio Escrig-Larena, Juan Francisco Aranda, Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Eva María Blanco, Joyce Días-Almeida, Gabriel Núñez, María Mittelbrunn
Healthy aging relies on a symbiotic host-microbiota relationship. The age-associated decline of the immune system can pose a threat to this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can affect host-microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the Tfamfl/flCd4Cre mouse model, we found that T cell failure compromised gut immunity leading to a decrease in T follicular cells and regulatory T cells (Treg cells) and an accumulation of highly proinflammatory and cytotoxic T cells. These alterations were associated with intestinal barrier disruption and gut dysbiosis. Microbiota depletion or adoptive transfer of total CD4 T cells or a Treg cell–enriched pool prevented gut barrier dysfunction and mitigated premature inflammaging and senescence, ultimately enhancing the health span in this mouse model. Thus, a competent CD4 T cell compartment is critical to ensure healthier aging by promoting host-microbiota mutualism and gut barrier integrity.
{"title":"CD4 T cell therapy counteracts inflammaging and senescence by preserving gut barrier integrity","authors":"Manuel M. Gómez de las Heras, Elisa Carrasco, Mario Pérez-Manrique, Naohiro Inohara, Sandra Delgado-Pulido, Álvaro Fernández-Almeida, María I. Gálvez-Castaño, Isaac Francos-Quijorna, Carolina Simó, Virginia García-Cañas, José Ignacio Escrig-Larena, Juan Francisco Aranda, Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Eva María Blanco, Joyce Días-Almeida, Gabriel Núñez, María Mittelbrunn","doi":"10.1126/sciimmunol.adv0985","DOIUrl":"10.1126/sciimmunol.adv0985","url":null,"abstract":"<div >Healthy aging relies on a symbiotic host-microbiota relationship. The age-associated decline of the immune system can pose a threat to this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can affect host-microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the <i>Tfam</i><sup>fl/fl</sup><i>Cd4</i><sup>Cre</sup> mouse model, we found that T cell failure compromised gut immunity leading to a decrease in T follicular cells and regulatory T cells (T<sub>reg</sub> cells) and an accumulation of highly proinflammatory and cytotoxic T cells. These alterations were associated with intestinal barrier disruption and gut dysbiosis. Microbiota depletion or adoptive transfer of total CD4 T cells or a T<sub>reg</sub> cell–enriched pool prevented gut barrier dysfunction and mitigated premature inflammaging and senescence, ultimately enhancing the health span in this mouse model. Thus, a competent CD4 T cell compartment is critical to ensure healthier aging by promoting host-microbiota mutualism and gut barrier integrity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adv0985","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756630","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}
Pub Date : 2025-08-01DOI: 10.1126/sciimmunol.aea8744
Thomas T. Xu, Shiv Pillai
LAG-3 dampens CD4+ T cell activation by disrupting CDε-Lck condensates and is a therapeutic target in both cancer and autoimmunity.
LAG-3通过破坏CDε-Lck凝聚体抑制CD4+ T细胞活化，是癌症和自身免疫的治疗靶点。
{"title":"A LAGging kiss leaves T cells cold","authors":"Thomas T. Xu, Shiv Pillai","doi":"10.1126/sciimmunol.aea8744","DOIUrl":"10.1126/sciimmunol.aea8744","url":null,"abstract":"<div >LAG-3 dampens CD4+ T cell activation by disrupting CDε-Lck condensates and is a therapeutic target in both cancer and autoimmunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 110","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758629","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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