Journal of immunology最新文献_第8页

Transcription Factor Activity Regulating Macrophage Heterogeneity during Skin Wound Healing. 转录因子活性调节皮肤伤口愈合过程中巨噬细胞的异质性

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-15 DOI: 10.4049/jimmunol.2400172

Mehrdad Zandigohar, Jingbo Pang, Alannah Rodrigues, Rita E Roberts, Yang Dai, Timothy J Koh

{"title":"Transcription Factor Activity Regulating Macrophage Heterogeneity during Skin Wound Healing.","authors":"Mehrdad Zandigohar, Jingbo Pang, Alannah Rodrigues, Rita E Roberts, Yang Dai, Timothy J Koh","doi":"10.4049/jimmunol.2400172","DOIUrl":"10.4049/jimmunol.2400172","url":null,"abstract":"Monocytes and macrophages (Mos/Mϕs) play diverse roles in wound healing by adopting a spectrum of functional phenotypes; however, the regulation of such heterogeneity remains poorly defined. We enhanced our previously published Bayesian inference TF activity model, incorporating both single-cell RNA sequencing and single-cell ATAC sequencing data to infer transcription factor (TF) activity in Mos/Mϕs during skin wound healing. We found that wound Mos/Mϕs clustered into early-stage Mos/Mϕs, late-stage Mϕs, and APCs, and that each cluster showed differential chromatin accessibility and differential predicted TF activity that did not always correlate with mRNA or protein expression. Network analysis revealed two highly connected large communities involving a total of 19 TFs, highlighting TF cooperation in regulating wound Mos/Mϕs. This analysis also revealed a small community populated by NR4A1 and NFKB1, supporting a proinflammatory link between these TFs. Importantly, we validated a proinflammatory role for NR4A1 activity during wound healing, showing that Nr4a1 knockout mice exhibit decreased inflammatory gene expression in early-stage wound Mos/Mϕs, along with delayed wound re-epithelialization and impaired granulation tissue formation. In summary, our study provides insight into TF activity that regulates Mo/Mϕ heterogeneity during wound healing and provides a rational basis for targeting Mo/Mϕ TF networks to alter phenotypes and improve healing.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"506-518"},"PeriodicalIF":3.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11300156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468611","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

ATP-elicited Cation Fluxes Promote Volume-regulated Anion Channel LRRC8/VRAC Transport cGAMP for Antitumor Immunity. ATP激发的阳离子通量促进体积调节阴离子通道LRRC8/VRAC转运cGAMP以增强抗肿瘤免疫力

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2300812

Li Wang, Limin Cao, Zhihong Li, Zhugui Shao, Xia Chen, Zhicheng Huang, Xiaoxiao He, Junke Zheng, Li Liu, Xin-Ming Jia, Hui Xiao

{"title":"ATP-elicited Cation Fluxes Promote Volume-regulated Anion Channel LRRC8/VRAC Transport cGAMP for Antitumor Immunity.","authors":"Li Wang, Limin Cao, Zhihong Li, Zhugui Shao, Xia Chen, Zhicheng Huang, Xiaoxiao He, Junke Zheng, Li Liu, Xin-Ming Jia, Hui Xiao","doi":"10.4049/jimmunol.2300812","DOIUrl":"10.4049/jimmunol.2300812","url":null,"abstract":"The cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells' cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-β response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-β response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-β response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC's obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"347-361"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283917","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

A RORE-dependent Intronic Enhancer in the IL-7 Receptor-α Locus Controls Glucose Metabolism via Vγ4+ γδT17 Cells. IL-7 受体-α基因座中依赖于 RORE 的非线性增强子通过 Vγ4+ γδT17 细胞控制葡萄糖代谢。

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2300450

Shizue Tani-Ichi, David Obwegs, Alice Yoshikawa, Hitomi Watanabe, Satsuki Kitano, Aki Ejima, Shinya Hatano, Hitoshi Miyachi, Guangwei Cui, Akihiro Shimba, Shinya Abe, Shohei Hori, Gen Kondoh, Sagar, Yasunobu Yoshikai, Koichi Ikuta

{"title":"A RORE-dependent Intronic Enhancer in the IL-7 Receptor-α Locus Controls Glucose Metabolism via Vγ4+ γδT17 Cells.","authors":"Shizue Tani-Ichi, David Obwegs, Alice Yoshikawa, Hitomi Watanabe, Satsuki Kitano, Aki Ejima, Shinya Hatano, Hitoshi Miyachi, Guangwei Cui, Akihiro Shimba, Shinya Abe, Shohei Hori, Gen Kondoh, Sagar, Yasunobu Yoshikai, Koichi Ikuta","doi":"10.4049/jimmunol.2300450","DOIUrl":"https://doi.org/10.4049/jimmunol.2300450","url":null,"abstract":"The IL-7R regulates the homeostasis, activation, and distribution of T cells in peripheral tissues. Although several transcriptional enhancers that regulate IL-7Rα expression in αβ T cells have been identified, enhancers active in γδ T cells remain unknown. In this article, we discovered an evolutionarily conserved noncoding sequence (CNS) in intron 2 of the IL-7Rα-chain (IL-7Rα) locus and named this region CNS9. CNS9 contained a conserved retinoic acid receptor-related orphan receptor (ROR)-responsive element (RORE) and exerted RORγt-dependent enhancer activity in vitro. Mice harboring point mutations in the RORE in CNS9 (CNS9-RORmut) showed reduced IL-7Rα expression in IL-17-producing Vγ4+ γδ T cells. In addition, the cell number and IL-17A production of Vγ4+ γδ T cells were reduced in the adipose tissue of CNS9-RORmut mice. Consistent with the reduction in IL-17A, CNS9-RORmut mice exhibited decreased IL-33 expression in the adipose tissue, resulting in fewer regulatory T cells and glucose intolerance. The CNS9-ROR motif was partially responsible for IL-7Rα expression in RORγt+ regulatory T cells, whereas IL-7Rα expression was unaffected in RORγt-expressing Vγ2+ γδ T cells, Th17 cells, type 3 innate lymphoid cells, and invariant NKT cells. Our results indicate that CNS9 is a RORΕ-dependent, Vγ4+ γδ T cell-specific IL-7Rα enhancer that plays a critical role in adipose tissue homeostasis via regulatory T cells, suggesting that the evolutionarily conserved RORΕ in IL-7Rα intron 2 may influence the incidence of type 2 diabetes.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"213 3","pages":"283-295"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975853","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

Both IRAK3 and IRAK1 Activate the MyD88-TRAF6 Pathway in Zebrafish. IRAK3 和 IRAK1 都能激活斑马鱼的 MyD88-TRAF6 通路

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2400054

Panwei Weng, Mengjiao Lan, Hao Zhang, Huiping Fan, Xiao Wang, Chenrui Ran, Zirui Yue, Jiaxuan Hu, Anlong Xu, Shengfeng Huang

{"title":"Both IRAK3 and IRAK1 Activate the MyD88-TRAF6 Pathway in Zebrafish.","authors":"Panwei Weng, Mengjiao Lan, Hao Zhang, Huiping Fan, Xiao Wang, Chenrui Ran, Zirui Yue, Jiaxuan Hu, Anlong Xu, Shengfeng Huang","doi":"10.4049/jimmunol.2400054","DOIUrl":"10.4049/jimmunol.2400054","url":null,"abstract":"IL-1R-associated kinases (IRAKs) are signal transducers of the TLR/IL-1R-MyD88-TRAF6 pathways. Vertebrates possess two IRAK lineages, IRAK1/2/3 and IRAK4. In mammals, IRAK4/IRAK1 and IRAK4/IRAK2 are pathway enhancers, whereas IRAK3 is a repressor. However, in bony fish, IRAK2 is absent, and it remains elusive how fish IRAK1/3/4 functionally differ from their mammalian counterparts. In this study, we explored this using the zebrafish model. First, we showed that in human 293T cells, zebrafish IRAK1 and IRAK4 were components of the Myddosome (MyD88-IRAK4-IRAK1) complex, with IRAK1 serving as a potent pathway enhancer. Then, we discovered two zebrafish IRAK3 variants: one (IRAK3a) contains an N-terminal Death domain, a middle pseudokinase domain, and a C-terminal TRAF6-binding domain, whereas the other (IRAK3b) lost both the kinase and TRAF6-binding domains. This truncation of IRAK3 variants could be a conserved phenomenon in fish, because it is also observed in trout and grass carp. We proceeded to show that zebrafish IRAK3a acts as a pathway enhancer by binding with MyD88 and TRAF6, but its activity is milder than IRAK1, possibly because it has no kinase activity. Zebrafish IRAK3b, however, plays a sheer negative role, apparently because of its lack of kinase and TRAF6-binding domains. Moreover, zebrafish IRAK3a/3b inhibit the activity of IRAK1/4, not by interacting with IRAK1/4 but possibly by competing for MyD88 and TRAF6. Finally, we have verified the essential activities of zebrafish IRAK1/3a/3b/4 in zebrafish cells and embryos. In summary, to our knowledge, our findings provide new insights into the molecular functions of fish IRAKs and the evolution of the IRAK functional modes in vertebrates.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"362-372"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283918","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

Cytotoxic CD4+ T Cells Are Induced during Infection with Chlamydia trachomatis. 在沙眼衣原体感染过程中诱导细胞毒性 CD4+ T 细胞

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2300131

Joanna Olivas, Caterina Nogueira, Jennifer Helble, Michael N Starnbach

{"title":"Cytotoxic CD4+ T Cells Are Induced during Infection with Chlamydia trachomatis.","authors":"Joanna Olivas, Caterina Nogueira, Jennifer Helble, Michael N Starnbach","doi":"10.4049/jimmunol.2300131","DOIUrl":"10.4049/jimmunol.2300131","url":null,"abstract":"Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infection in both men and women. Immunity to C. trachomatis involves many cell types, but CD4+ T cells play a key role in protecting the host during natural infection. Specifically, IFN-γ production by CD4+ T cells is the main effector responsible for bacterial clearance, yet the exact mechanism by which IFN-γ confers protection is poorly defined. In our efforts to define the specific mechanisms for bacterial clearance, we now show that IFN-γ upregulates expression of MHC class II (MHCII) on nonhematopoietic cells during C. trachomatis infection in vivo. We also find that MHCII expression on epithelial cells of the upper genital tract contributes to the efficient clearance of bacteria mediated by pathogen-specific CD4+ Th1 cells. As we further cataloged the protective mechanisms of C. trachomatis-specific CD4+ T cells, we found that the T cells also express granzyme B (GzmB) when coincubated with infected cells. In addition, during C. trachomatis infection of mice, primed activated-naive CD4+ Th1 cells displayed elevated granzyme transcripts (GzmA, GzmB, GzmM, GzmK, GzmC) compared with memory CD4+ T cells in vivo. Finally, using intracellular cytokine staining and a GzmB-/- mouse strain, we show that C. trachomatis-specific CD4+ Th1 cells express GzmB upon Ag stimulation, and that this correlates with Chlamydia clearance in vivo. Together these results have led us to conclude that Chlamydia-specific CD4+ Th1 cells develop cytotoxic capacity through engagement with nonhematopoietic MHCII, and this correlates to C. trachomatis clearance.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"328-338"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11279525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437009","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

Top Reads. 热门阅读

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2490008

引用次数: 0

Single-Cell RNA Sequencing Identifies WARS1+ Mesenchymal Stem Cells with Enhanced Immunomodulatory Capacity and Improved Therapeutic Efficacy. 单细胞 RNA 测序发现 WARS1+ 间充质干细胞具有更强的免疫调节能力和更好的疗效

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2300752

Xiangxiao Li, Fengjiao Zhang, Libo Sun, Xiaojie Cai, Fangzhou Lou, Yang Sun, Min Gao, Zhikai Wang, Sibei Tang, Li Fan, Yue Wu, Xinping Jin, Siyu Deng, Zhenyao Xu, Xuxu Sun, Qun Li, Honglin Wang

{"title":"Single-Cell RNA Sequencing Identifies WARS1+ Mesenchymal Stem Cells with Enhanced Immunomodulatory Capacity and Improved Therapeutic Efficacy.","authors":"Xiangxiao Li, Fengjiao Zhang, Libo Sun, Xiaojie Cai, Fangzhou Lou, Yang Sun, Min Gao, Zhikai Wang, Sibei Tang, Li Fan, Yue Wu, Xinping Jin, Siyu Deng, Zhenyao Xu, Xuxu Sun, Qun Li, Honglin Wang","doi":"10.4049/jimmunol.2300752","DOIUrl":"10.4049/jimmunol.2300752","url":null,"abstract":"Psoriasis is a common inflammatory skin disorder with no cure. Mesenchymal stem cells (MSCs) have immunomodulatory properties for psoriasis, but the therapeutic efficacies varied, and the molecular mechanisms were unknown. In this study, we improved the efficacy by enhancing the immunomodulatory effects of umbilical cord-derived MSCs (UC-MSCs). UC-MSCs stimulated by TNF-α and IFN-γ exhibited a better therapeutic effect in a mouse model of psoriasis. Single-cell RNA sequencing revealed that the stimulated UC-MSCs overrepresented a subpopulation expressing high tryptophanyl-tRNA synthetase 1 (WARS1). WARS1-overexpressed UC-MSCs treat psoriasis-like skin inflammation more efficiently than control UC-MSCs by restraining the proinflammatory macrophages. Mechanistically, WARS1 maintained a RhoA-Akt axis and governed the immunomodulatory properties of UC-MSCs. Together, we identify WARS1 as a master regulator of UC-MSCs with enhanced immunomodulatory capacities, which paves the way for the directed modification of UC-MSCs for escalated therapeutic efficacy.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"257-267"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296212","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

Obesity Inhibits Alveolar Macrophage Responses to Pseudomonas aeruginosa Pneumonia via Upregulation of Prostaglandin E2 in Male, but Not Female, Mice. 肥胖通过上调雄性小鼠而非雌性小鼠的前列腺素 E2抑制肺泡巨噬细胞对铜绿假单胞菌肺炎的反应

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2400140

Gabrielle P Entrup, Aayush Unadkat, Helen I Warheit-Niemi, Brooke Thomas, Stephen J Gurczynski, Yuxiao Cui, Andrew M Smith, Katherine A Gallagher, Bethany B Moore, Kanakadurga Singer

{"title":"Obesity Inhibits Alveolar Macrophage Responses to Pseudomonas aeruginosa Pneumonia via Upregulation of Prostaglandin E2 in Male, but Not Female, Mice.","authors":"Gabrielle P Entrup, Aayush Unadkat, Helen I Warheit-Niemi, Brooke Thomas, Stephen J Gurczynski, Yuxiao Cui, Andrew M Smith, Katherine A Gallagher, Bethany B Moore, Kanakadurga Singer","doi":"10.4049/jimmunol.2400140","DOIUrl":"10.4049/jimmunol.2400140","url":null,"abstract":"Obesity is associated with increased morbidity and mortality during bacterial pneumonia. Cyclooxygenase-2 (COX-2) and PGE2 have been shown to be upregulated in patients who are obese. In this study, we investigated the role of obesity and PGE2 in bacterial pneumonia and how inhibition of PGE2 improves antibacterial functions of macrophages. C57BL/6J male and female mice were fed either a normal diet (ND) or high-fat diet (HFD) for 16 wk. After this time, animals were infected with Pseudomonas aeruginosa in the lung. In uninfected animals, alveolar macrophages were extracted for either RNA analysis or to be cultured ex vivo for functional analysis. HFD resulted in changes in immune cell numbers in both noninfected and infected animals. HFD animals had increased bacterial burden compared with ND animals; however, male HFD animals had higher bacterial burden compared with HFD females. Alveolar macrophages from HFD males had decreased ability to phagocytize and kill bacteria and were shown to have increased cyclooxygenase-2 and PGE2. Treating male, but not female, alveolar macrophages with PGE2 leads to increases in cAMP and decreased bacterial phagocytosis. Treatment with lumiracoxib-conjugated nanocarriers targeting alveolar macrophages improves bacterial phagocytosis and clearance in both ND and HFD male animals. Our study highlights that obesity leads to worse morbidity during bacterial pneumonia in male mice because of elevated PGE2. In addition, we uncover a sex difference in both obesity and infection, because females produce high basal PGE2 but because of a failure to signal via cAMP do not display impaired phagocytosis.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"317-327"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437011","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

Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development. 内质网应激反应介质 IRE-1α 促进宿主树突状细胞在移植物抗宿主疾病发展中的作用

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2300616

Hee-Jin Choi, Yongxia Wu, Brianyell McDaniel Mims, Allison Pugel, Chih-Hang Anthony Tang, Linlu Tian, Chih-Chi Andrew Hu, Xue-Zhong Yu

{"title":"Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development.","authors":"Hee-Jin Choi, Yongxia Wu, Brianyell McDaniel Mims, Allison Pugel, Chih-Hang Anthony Tang, Linlu Tian, Chih-Chi Andrew Hu, Xue-Zhong Yu","doi":"10.4049/jimmunol.2300616","DOIUrl":"10.4049/jimmunol.2300616","url":null,"abstract":"Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"384-393"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11415232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306133","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

B Cells of Early-life Origin Defined by RAG2-based Lymphoid Cell Tracking under Native Hematopoietic Conditions. 在原生造血条件下通过基于 RAG2 的淋巴细胞追踪确定生命早期起源的 B 细胞

IF 3.6 3区医学

Journal of immunology Pub Date : 2024-08-01 DOI: 10.4049/jimmunol.2400072

Keiko Fujisaki, Shogo Okazaki, Shuhei Ogawa, Miyama Takeda, Eiji Sugihara, Kenichi Imai, Seiya Mizuno, Satoru Takahashi, Ryo Goitsuka

{"title":"B Cells of Early-life Origin Defined by RAG2-based Lymphoid Cell Tracking under Native Hematopoietic Conditions.","authors":"Keiko Fujisaki, Shogo Okazaki, Shuhei Ogawa, Miyama Takeda, Eiji Sugihara, Kenichi Imai, Seiya Mizuno, Satoru Takahashi, Ryo Goitsuka","doi":"10.4049/jimmunol.2400072","DOIUrl":"10.4049/jimmunol.2400072","url":null,"abstract":"During the perinatal period, the immune system sets the threshold to select either response or tolerance to environmental Ags, which leads to the potential to provide a lifetime of protection and health. B-1a B cells have been demonstrated to develop during this perinatal time window, showing a unique and restricted BCR repertoire, and these cells play a major role in natural Ab secretion and immune regulation. In the current study, we developed a highly efficient temporally controllable RAG2-based lymphoid lineage cell labeling and tracking system and applied this system to understand the biological properties and contribution of B-1a cells generated at distinct developmental periods to the adult B-1a compartments. This approach revealed that B-1a cells with a history of RAG2 expression during the embryonic and neonatal periods dominate the adult B-1a compartment, including those in the bone marrow (BM), peritoneal cavity, and spleen. Moreover, the BCR repertoire of B-1a cells with a history of RAG2 expression during the embryonic period was restricted, becoming gradually more diverse during the neonatal period, and then heterogeneous at the adult stage. Furthermore, more than half of plasmablasts/plasma cells in the adult BM had embryonic and neonatal RAG2 expression histories. Moreover, BCR analysis revealed a high relatedness between BM plasmablasts/plasma cells and B-1a cells derived from embryonic and neonatal periods, suggesting that these cell types have a common origin. Taken together, these findings define, under native hematopoietic conditions, the importance in adulthood of B-1a cells generated during the perinatal period.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"296-305"},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317537","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