Journal of immunology最新文献_第2页

IL-1β Induces Human Endothelial Surface Expression of IL-15 by Relieving let-7c-3p Suppression of Protein Translation. IL-1β 通过缓解 let-7c-3p 对蛋白质翻译的抑制，诱导人内皮细胞表面表达 IL-15。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-20 DOI: 10.4049/jimmunol.2400331

Clancy W Mullan, Luanna Summer, Francesc Lopez-Giraldez, Zuzana Tobiasova, Thomas D Manes, Shruthi Yasothan, Guiyu Song, Daniel Jane-Wit, W Mark Saltzman, Jordan S Pober

{"title":"IL-1β Induces Human Endothelial Surface Expression of IL-15 by Relieving let-7c-3p Suppression of Protein Translation.","authors":"Clancy W Mullan, Luanna Summer, Francesc Lopez-Giraldez, Zuzana Tobiasova, Thomas D Manes, Shruthi Yasothan, Guiyu Song, Daniel Jane-Wit, W Mark Saltzman, Jordan S Pober","doi":"10.4049/jimmunol.2400331","DOIUrl":"10.4049/jimmunol.2400331","url":null,"abstract":"Expression of IL-15 on the surface of human graft endothelial cells (ECs) bound to the IL-15Rα subunit can increase the activation of CTLs, potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1β synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-κB. In this article, we report that cultured human ECs express eight differently spliced IL-15 transcripts. Remarkably, IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1β causes an NF-κB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p anti-miR can induce EC surface expression of IL-15/IL-15Rα in the absence of complement activation or of IL-1, enabling IL-15 transpresentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for transpresentation.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Circulating Immune Cells from Early- and Late-onset Pre-eclampsia Displays Distinct Profiles with Differential Impact on Endothelial Activation. 早发和晚发子痫前期的循环免疫细胞显示出不同的特征，对内皮激活的影响也不同。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-20 DOI: 10.4049/jimmunol.2400196

Elsa Bernier, Camille Couture, Anna Borchers, Marie-Eve Brien, Charles H Graham, Sylvie Girard

{"title":"Circulating Immune Cells from Early- and Late-onset Pre-eclampsia Displays Distinct Profiles with Differential Impact on Endothelial Activation.","authors":"Elsa Bernier, Camille Couture, Anna Borchers, Marie-Eve Brien, Charles H Graham, Sylvie Girard","doi":"10.4049/jimmunol.2400196","DOIUrl":"https://doi.org/10.4049/jimmunol.2400196","url":null,"abstract":"Pre-eclampsia (PE) affects 5-8% of pregnancies and has detrimental effects on maternal-fetal health. PE is characterized by de novo hypertension after 20 wk of gestation and end-organ damage. Systemic inflammatory imbalance has been associated with PE, but its contribution to the pathology is poorly understood. Our objective was to investigate maternal systemic immune changes in early-onset PE (EOPE) and late-onset PE (LOPE) versus uncomplicated pregnancies (control [CTRL]), and their contribution to endothelial activation, hallmark of hypertension. Blood samples were analyzed by flow cytometry, multiplex assay, intracellular cytokine staining, and single-cell RNA sequencing. We performed cocultures between circulating immune cells and HUVECs to assess endothelial activation. We found that EOPE had decreased regulatory T cells (4.64±0.33, p < 0.05) and monocytes (33.92±3.08, p < 0.01), whereas LOPE had decreased regulatory T cells (4.60±0.30, p < 0.05) and Th2 cells (7.50±0.62, p < 0.01) versus CTRL. Compared to CTRL, elevated cytokines/chemokines, and growth factors were observed in LOPE, whereas EOPE primarily showed decreased levels. Using intracellular cytokine staining, we observed more monocytes producing IL-12, TNF-α, and IL-1β (all p < 0.05) in LOPE versus CTRL. At the transcriptomic level, we found differentially expressed genes between EOPE and CTRL, predominantly related to upregulation of immune activation pathways. Lastly, EOPE PBMCs induced heightened endothelial activation in vitro observed by increased ICAM-1 and ET-1 (p < 0.05), whereas LOPE PBMCs required LPS stimulation. Although significant proteomic changes are observed in the LOPE group, the EOPE displayed changes mostly at the transcriptomic levels and could induce endothelial activation in vitro.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rapamycin Prevents Expansion of Costimulation Blockade-resistant CD8+ Alloreactive Memory Cells following Depletional Induction in Renal Transplant Recipients. 雷帕霉素能防止肾移植受者在去势诱导后扩增抗成本刺激阻断剂的 CD8+ Alloreactive 记忆细胞

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-20 DOI: 10.4049/jimmunol.2400146

Shu Li, Qimeng Gao, He Xu, Allan D Kirk

{"title":"Rapamycin Prevents Expansion of Costimulation Blockade-resistant CD8+ Alloreactive Memory Cells following Depletional Induction in Renal Transplant Recipients.","authors":"Shu Li, Qimeng Gao, He Xu, Allan D Kirk","doi":"10.4049/jimmunol.2400146","DOIUrl":"https://doi.org/10.4049/jimmunol.2400146","url":null,"abstract":"Alemtuzumab induction with belatacept/rapamycin-based maintenance immunotherapy (ABR) prevents kidney allograft rejection and specifically limits early costimulation blockade-resistant rejection (CoBRR). To evaluate the mechanisms by which this regimen alters CoBRR, we characterized the phenotype and functional response of preexisting memory cells to allogeneic endothelial cells using intracellular cytokine staining and flow cytometry. IL-7-induced lymphocyte proliferation in the presence or absence of rapamycin was assessed to characterize the phenotype of proliferating cells. Lymphocytes from 40 recipients who underwent transplant using the ABR regimen were studied longitudinally. The rapid immunoresponses of preexisting alloreactive cells to allogeneic endothelial cells were predominantly CD8+TNF-α+/IFN-γ+ cells. These cells were effector memory (TEM) and terminally differentiated effector memory cells lacking CD28 expression, and most were CD57+PD1-. Neither rapamycin nor belatacept directly inhibited these cells. IL-7, a cytokine induced during lymphopenia postdepletion, provoked dramatic CD8+ TEM cell proliferation and a low level of CD8+CD57+PD1- cell expansion in vitro. The IL-7 stimulation induced CD8+ cell mTOR phosphorylation, and rapamycin treatment markedly inhibited IL-7-induced TEM and CD57+PD1- cell expansion. This effect was evident in patients receiving the ABR in that the repopulation of CD8+CD57+PD1- TEM cells was substantially suppressed for at least 36 mo after transplant. These findings help define one mechanism by which a costimulation blockade/rapamycin-based therapy following alemtuzumab induction minimizes CoBRR, namely that in the presence of rapamycin, costimulation-resistant alloreactive cells are disproportionately ineffective at repopulating following post-transplant T cell depletion.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chitinase 3-like-1 Inhibits Innate Antitumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα- and CD24-Siglec10-Mediated Phagocytosis. 几丁质酶 3-like-1 通过调节 CD47-SIRPα 和 CD24-Siglec10 介导的吞噬作用抑制先天性抗肿瘤和组织重塑免疫反应

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-18 DOI: 10.4049/jimmunol.2400035

Bing Ma, Suchitra Kamle, Takayuki Sadanaga, Chang-Min Lee, Joyce H Lee, Daniel C Yee, Zhou Zhu, Edwin K Silverman, Dawn L DeMeo, Augustine M K Choi, Chun Geun Lee, Jack A Elias

{"title":"Chitinase 3-like-1 Inhibits Innate Antitumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα- and CD24-Siglec10-Mediated Phagocytosis.","authors":"Bing Ma, Suchitra Kamle, Takayuki Sadanaga, Chang-Min Lee, Joyce H Lee, Daniel C Yee, Zhou Zhu, Edwin K Silverman, Dawn L DeMeo, Augustine M K Choi, Chun Geun Lee, Jack A Elias","doi":"10.4049/jimmunol.2400035","DOIUrl":"https://doi.org/10.4049/jimmunol.2400035","url":null,"abstract":"Innate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in chronic obstructive pulmonary disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. In this study, we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage \"eat me\" signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are associated with CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and inhibition of the accumulation and phosphorylation of cytoskeleton-regulating nonmuscle myosin IIa. This inhibition of innate immune responses such as phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases such as COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell costimulation, and regulate a number of other oncogenic and inflammation pathways suggests that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD, and other disorders.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-cell and Spatial Transcriptomic Analyses Implicate Formation of the Immunosuppressive Microenvironment during Breast Tumor Progression. 单细胞和空间转录组分析暗示乳腺肿瘤进展过程中免疫抑制微环境的形成

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-16 DOI: 10.4049/jimmunol.2400025

Fengfeng Cai, YuanYuan Li, Hui Liu, Judong Luo

{"title":"Single-cell and Spatial Transcriptomic Analyses Implicate Formation of the Immunosuppressive Microenvironment during Breast Tumor Progression.","authors":"Fengfeng Cai, YuanYuan Li, Hui Liu, Judong Luo","doi":"10.4049/jimmunol.2400025","DOIUrl":"https://doi.org/10.4049/jimmunol.2400025","url":null,"abstract":"Ductal carcinoma in situ and invasive ductal carcinoma represent two stages of breast cancer progression. A multitude of studies have shown that genomic instability increases during tumor development, as manifested by higher mutation and copy number variation rates. The advent of single-cell and spatial transcriptomics has enabled the investigation of the subtle differences in cellular states during the tumor progression at single-cell level, thereby providing more nuanced understanding of the intercellular interactions within the solid tumor. However, the evolutionary trajectory of tumor cells and the establishment of the immunosuppressive microenvironment during breast cancer progression remain unclear. In this study, we performed an exploratory analysis of the single-cell sequencing dataset of 13 ductal carcinoma in situ and invasive ductal carcinoma samples. We revealed that tumor cells became more malignant and aggressive during their progression, and T cells transited to an exhausted state. The tumor cells expressed various coinhibitory ligands that interacted with the receptors of immune cells to create an immunosuppressive tumor microenvironment. Furthermore, spatial transcriptomics data confirmed the spatial colocalization of tumor and immune cells, as well as the expression of the coinhibitory ligand-receptor pairs. Our analysis provides insights into the cellular and molecular mechanism underlying the formation of the immunosuppressive landscape during two typical stages of breast cancer progression.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-10 Is Critical for Regulation of Cytotoxic CD4+NKG7+ T Cells in Lung Allograft Rejection but Is Not Required for Allograft Acceptance. IL-10对调节肺移植排斥反应中的细胞毒性CD4+NKG7+ T细胞至关重要，但并非接受移植所必需。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400279

Antu Das, Xingan Wang, Kaitlyn Devonshire, Emily J Lyons, Iulia Popescu, Zihe Zhou, Jingmei Li, John Sembrat, Joseph Pilewski, Chunbin Zou, Jonathan K Alder, Bill B Chen, Mark E Snyder, John F McDyer

{"title":"IL-10 Is Critical for Regulation of Cytotoxic CD4+NKG7+ T Cells in Lung Allograft Rejection but Is Not Required for Allograft Acceptance.","authors":"Antu Das, Xingan Wang, Kaitlyn Devonshire, Emily J Lyons, Iulia Popescu, Zihe Zhou, Jingmei Li, John Sembrat, Joseph Pilewski, Chunbin Zou, Jonathan K Alder, Bill B Chen, Mark E Snyder, John F McDyer","doi":"10.4049/jimmunol.2400279","DOIUrl":"10.4049/jimmunol.2400279","url":null,"abstract":"Lung transplant remains the primary therapeutic option for patients with end-stage lung disease, but long-term survival rates remain suboptimal compared with other solid organ transplants. Acute cellular rejection (ACR) is a significant challenge in lung transplant recipients, with T cell-mediated mechanisms playing a major role. IL-10 is known for its immunoregulatory function, although its specific role in lung allograft rejection remains unclear. Using the mouse orthotopic lung transplant model, we investigated the role of IL-10 in regulating alloeffector T cell responses. Unexpectedly, we found that IL-10 was not required for early costimulation blockade-induced allograft acceptance. However, IL-10 deficiency or blockade resulted in increased CD4+ T cell numbers, proliferation, graft infiltration, and alloeffector responses. In the absence of IL-10, CD4+ T cell responses predominated over CD8 responses during ACR in contrast to wild-type mice. Type 1 immunity (IFN-γ) responses along with elevated CD4+NKG7+ and CD4+CD107a+ responses predominated during ACR, highlighting a critical regulatory role for IL-10 in modulating CD4+ T cell alloimmune responses. We further demonstrated increased colocalization of NKG7 and CD107a in CD4+ T cells from IL-10-deficient allografts, suggesting coordination in cytotoxic activity. Together, our findings highlight a critical role for IL-10 in regulation of cytotoxic CD4+NKG7+ T cells, an effector population that needs further investigation to elucidate their role in lung allograft rejection.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Renal IL-23-Dependent Type 3 Innate Lymphoid Cells Link Crystal-induced Intrarenal Inflammasome Activation with Kidney Fibrosis. 肾脏 IL-23 依赖性 3 型先天性淋巴细胞将晶体诱导的肾内炎症体激活与肾脏纤维化联系起来

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400041

Teresa M Frasconi, Christian Kurts, Ermanila Dhana, Romina Kaiser, Miriam Reichelt, Veronika Lukacs-Kornek, Peter Boor, Anja E Hauser, Anna Pascual-Reguant, Sammy Bedoui, Jan-Eric Turner, Janine Becker-Gotot, Isis Ludwig-Portugall

{"title":"Renal IL-23-Dependent Type 3 Innate Lymphoid Cells Link Crystal-induced Intrarenal Inflammasome Activation with Kidney Fibrosis.","authors":"Teresa M Frasconi, Christian Kurts, Ermanila Dhana, Romina Kaiser, Miriam Reichelt, Veronika Lukacs-Kornek, Peter Boor, Anja E Hauser, Anna Pascual-Reguant, Sammy Bedoui, Jan-Eric Turner, Janine Becker-Gotot, Isis Ludwig-Portugall","doi":"10.4049/jimmunol.2400041","DOIUrl":"10.4049/jimmunol.2400041","url":null,"abstract":"Chronic inflammasome activation in mononuclear phagocytes (MNPs) promotes fibrosis in various tissues, including the kidney. The cellular and molecular links between the inflammasome and fibrosis are unclear. To address this question, we fed mice lacking various immunological mediators an adenine-enriched diet, which causes crystal precipitation in renal tubules, crystal-induced inflammasome activation, and renal fibrosis. We found that kidney fibrosis depended on an intrarenal inflammasome-dependent type 3 immune response driven by its signature transcription factor Rorc (retinoic acid receptor-related orphan receptor C gene), which was partially carried out by type 3 innate lymphoid cells (ILC3s). The role of ILCs in the kidney is less well known than in other organs, especially that of ILC3. In this article, we describe that depletion of ILCs or genetic deficiency for Rorc attenuated kidney inflammation and fibrosis. Among the inflammasome-derived cytokines, only IL-1β expanded ILC3 and promoted fibrosis, whereas IL-18 caused differentiation of NKp46+ ILC3. Deficiency of the type 3 maintenance cytokine, IL-23, was more protective than IL-1β inhibition, which may be explained by the downregulation of the IL-1R, but not of the IL-23R, by ILC3 early in the disease, allowing persistent sensing of IL-23. Mechanistically, ILC3s colocalized with renal MNPs in vivo as shown by multiepitope-ligand cartography. Cell culture experiments indicated that renal ILC3s caused renal MNPs to increase TGF-β production that stimulated fibroblasts to produce collagen. We conclude that ILC3s link inflammasome activation with kidney inflammation and fibrosis and are regulated by IL-1β and IL-23.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Longitudinal Intravascular Antibody Labeling Identified Regulatory T Cell Recruitment as a Therapeutic Target in a Mouse Model of Lung Cancer. 纵向血管内抗体标记发现调节性 T 细胞招募是肺癌小鼠模型的治疗靶点

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400268

Sean-Luc Shanahan, Nikesh Kunder, Charles Inaku, Natalie B Hagan, Grace Gibbons, Nicolas Mathey-Andrews, Gayathri Anandappa, Shawn Soares, Kristen E Pauken, Tyler Jacks, Jason M Schenkel

{"title":"Longitudinal Intravascular Antibody Labeling Identified Regulatory T Cell Recruitment as a Therapeutic Target in a Mouse Model of Lung Cancer.","authors":"Sean-Luc Shanahan, Nikesh Kunder, Charles Inaku, Natalie B Hagan, Grace Gibbons, Nicolas Mathey-Andrews, Gayathri Anandappa, Shawn Soares, Kristen E Pauken, Tyler Jacks, Jason M Schenkel","doi":"10.4049/jimmunol.2400268","DOIUrl":"10.4049/jimmunol.2400268","url":null,"abstract":"Anticancer immunity is predicated on leukocyte migration into tumors. Once recruited, leukocytes undergo substantial reprogramming to adapt to the tumor microenvironment. A major challenge in the field is distinguishing recently recruited from resident leukocytes in tumors. In this study, we developed an intravascular Ab technique to label circulating mouse leukocytes before they migrate to tissues, providing unprecedented insight into the kinetics of recruitment. This approach unveiled the substantial role of leukocyte migration in tumor progression using a preclinical mouse model of lung adenocarcinoma. Regulatory T cells (Tregs), critical mediators of immunosuppression, were continuously and rapidly recruited into tumors throughout cancer progression. Moreover, leukocyte trafficking depended on the integrins CD11a/CD49d, and CD11a/CD49d blockade led to significant tumor burden reduction in mice. Importantly, preventing circulating Treg recruitment through depletion or sequestration in lymph nodes was sufficient to decrease tumor burden, indicating that Treg migration was crucial for suppressing antitumor immunity. These findings underscore the dynamic nature of the immune compartment within mouse lung tumors and demonstrate the relevance of a temporal map of leukocyte recruitment into tumors, thereby advancing our understanding of leukocyte migration in the context of tumor development.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

C/EBPδ Mediates Immunity to Renal Autoinflammatory Disorders in a Stage-specific Manner. C/EBPδ以特定阶段的方式介导肾脏自身炎症性疾病的免疫力

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2400124

Ipsita Dey, Yang Li, Tiffany C Taylor, Doureradjou Peroumal, Nariaki Asada, Ulf Panzer, Partha S Biswas, Esta Sterneck, Sarah L Gaffen

{"title":"C/EBPδ Mediates Immunity to Renal Autoinflammatory Disorders in a Stage-specific Manner.","authors":"Ipsita Dey, Yang Li, Tiffany C Taylor, Doureradjou Peroumal, Nariaki Asada, Ulf Panzer, Partha S Biswas, Esta Sterneck, Sarah L Gaffen","doi":"10.4049/jimmunol.2400124","DOIUrl":"10.4049/jimmunol.2400124","url":null,"abstract":"Kidney disease represents a major medical and economic burden for which improved treatments are urgently needed. Emerging data have implicated Th17 cells and IL-17 signaling in the underlying pathogenesis of autoantibody-induced glomerulonephritis (AGN). However, the downstream transduction pathways mediated by IL-17 in autoimmunity are not well defined. In this article, we show that CCAAT/enhancer-binding protein (C/EBP) δ is elevated in kidney biopsies from multiple manifestations of human AGN. C/EBPδ is similarly upregulated in a mouse model of anti-glomerular basement membrane protein-mediated kidney disease, and Cebpd-/- mice were fully refractory to disease. Although C/EBPδ is expressed in a variety of cell types, C/EBPδ was required only in the radioresistant compartment to drive GN pathology. C/EBPδ induced expression of several IL-17-induced kidney injury markers and cytokines implicated in disease, including Il6 and Lcn2. Because mouse AGN models do not progress to fibrosis, we employed a nephrotoxic injury model using aristolochic acid I to assess the contribution of the IL-17-C/EBPδ pathway to renal fibrotic events. Surprisingly, deficiency of either C/EBPδ or the IL-17 receptor caused kidney fibrosis to be enhanced. Thus, C/EBPδ and IL-17 play divergent and apparently stage-specific roles in the pathogenesis of kidney disease.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulatory T Cell Insufficiency in Autoimmune Diabetes Is Driven by Selective Loss of Neuropilin-1 on Intraislet Regulatory T Cells. 自身免疫性糖尿病的调节性 T 细胞不足是由胰岛内调节性 T 细胞神经蛋白酶-1 的选择性丧失驱动的。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-09-15 DOI: 10.4049/jimmunol.2300216

Stephanie Grebinoski, Gwenyth Pieklo, Qianxia Zhang, Anabelle Visperas, Jian Cui, Jordana Goulet, Hanxi Xiao, Erin A Brunazzi, Carly Cardello, Andrés A Herrada, Jishnu Das, Creg J Workman, Dario A A Vignali

{"title":"Regulatory T Cell Insufficiency in Autoimmune Diabetes Is Driven by Selective Loss of Neuropilin-1 on Intraislet Regulatory T Cells.","authors":"Stephanie Grebinoski, Gwenyth Pieklo, Qianxia Zhang, Anabelle Visperas, Jian Cui, Jordana Goulet, Hanxi Xiao, Erin A Brunazzi, Carly Cardello, Andrés A Herrada, Jishnu Das, Creg J Workman, Dario A A Vignali","doi":"10.4049/jimmunol.2300216","DOIUrl":"10.4049/jimmunol.2300216","url":null,"abstract":"Approaches to reverse or limit regulatory T cell (Treg) insufficiency are of great interest for development of immunotherapeutic treatments for autoimmune patients, including type 1 diabetes. Treg insufficiency is heavily implicated in the progression of autoimmune diabetes in the NOD mouse model and is characterized by defects in Treg numbers, development, and/or function. Utilizing a Treg-centric screen, we show that intraislet Tregs have a uniquely dysfunctional phenotype, hallmarked by an almost complete lack of neuropilin-1 (Nrp1), a cell surface receptor required to maintain Treg stability. Intraislet Nrp1- Tregs exhibit hallmark features of fragility, including reduced suppressive capacity, decreased CD73 and Helios, and increased Rorγt and Tbet. Intraislet Nrp1- Tregs also exhibit decreased Foxp3 expression on a per cell basis, suggesting that Nrp1 may also be required for long-term Treg stability. Mechanistically, Treg-restricted augmentation of Nrp1 expression limited the onset of autoimmune diabetes in NOD mice suggesting that Nrp1 critically impacts intraislet Treg function. Transcriptional analysis showed that Nrp1 restoration led to an increase in markers and pathways of TCR signaling, survival, and suppression, and when Nrp1 protein expression is examined by cellular indexing of transcriptomes and epitopes by sequencing, significant differences were observed between Nrp1+ and Nrp1- Tregs in all tissues, particularly in markers of Treg fragility. This translated into substantive differences between Nrp1+ and Nrp1- Tregs that afforded the former with a competitive advantage in the islets. Taken together, these data suggest that maintenance of Nrp1 expression and signaling on Tregs limits diabetes onset and may serve as a strategy to combat Treg insufficiency in autoimmune disease.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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