Journal of immunology最新文献_第5页

HLA-E/peptide complexes differentially interact with NKG2A/CD94 and T cell receptors. HLA-E/肽复合物与NKG2A/CD94和T细胞受体的相互作用存在差异。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-14 DOI: 10.1093/jimmun/vkae068

Linda Voogd, Remco L van den Broek, Marjolein van Wolfswinkel, Kees L M C Franken, Paula Ruibal, Willem Jespers, Judith Leitner, Peter Steinberger, Gerard J P van Westen, Tom H M Ottenhoff, Simone A Joosten

{"title":"HLA-E/peptide complexes differentially interact with NKG2A/CD94 and T cell receptors.","authors":"Linda Voogd, Remco L van den Broek, Marjolein van Wolfswinkel, Kees L M C Franken, Paula Ruibal, Willem Jespers, Judith Leitner, Peter Steinberger, Gerard J P van Westen, Tom H M Ottenhoff, Simone A Joosten","doi":"10.1093/jimmun/vkae068","DOIUrl":"https://doi.org/10.1093/jimmun/vkae068","url":null,"abstract":"The virtually monomorphic antigen presentation molecule HLA-E can present self- and non-self peptides to the NKG2A/CD94 co-receptor inhibitory complex expressed on natural killer (NK) cells and to T cell receptors (TCRs) expressed on T cells. HLA-E presents self-peptides to NKG2A/CD94 to regulate tissue homeostasis, whereas HLA-E restricted T cells mediate regulatory and cytotoxic responses toward pathogen-infected cells. In this study, we directly compared HLA-E/peptide recognition and signaling between NKG2A/CD94 and 2 HLA-E restricted TCRs that can recognize self-peptides or identical peptide mimics from the viral UL40 protein of cytomegalovirus using position substituted peptide variants. We show that position 7 is critical for interaction with NKG2A/CD94, whereas position 8 is important for interaction with the TCRs. The Arginine at position 5 of these peptides is an essential residue for recognition by both receptors. Thus, NKG2A/CD94 and TCRs have different requirements for recognition of peptides presented in HLA-E.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630609","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

The transcription factor RORα is required for the development of type 1 innate lymphoid cells in adult bone marrow. 转录因子RORα是成人骨髓中1型先天淋巴样细胞发育所必需的。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-13 DOI: 10.1093/jimmun/vkaf001

Shinya Abe, Moe Kagao, Takuma Asahi, Ryoma Kato, Shizue Tani-Ichi, Akihiro Shimba, Riki Ishibashi, Hitoshi Miyachi, Satsuki Kitano, Masaki Miyazaki, Hans-Reimer Rodewald, Fumiko Toyoshima, Koichi Ikuta

{"title":"The transcription factor RORα is required for the development of type 1 innate lymphoid cells in adult bone marrow.","authors":"Shinya Abe, Moe Kagao, Takuma Asahi, Ryoma Kato, Shizue Tani-Ichi, Akihiro Shimba, Riki Ishibashi, Hitoshi Miyachi, Satsuki Kitano, Masaki Miyazaki, Hans-Reimer Rodewald, Fumiko Toyoshima, Koichi Ikuta","doi":"10.1093/jimmun/vkaf001","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf001","url":null,"abstract":"Type 1 innate lymphoid cells (ILC1s) respond to infections and tumors by producing IFN-γ. Although RAR-related orphan receptor α (RORα) is required for ILC2s and some ILC3s, its role in ILC1 development remains controversial. To investigate the role of RORα in ILC1s, we analyzed bone marrow (BM) chimeras of RORα-deficient mice. ILC1s derived from RORα-deficient BM cells were significantly reduced in various tissues, including the intestine, indicating a hematopoietic cell-intrinsic need for RORα in ILC1 development. Developmental stage-specific RORα-deficient mice showed a decrease in adult liver and BM IL-7R+ ILC1s and an increase in BM NK cells, whereas fetal liver ILC1s and adult liver IL-7R- ILC1s remained unchanged. Furthermore, RORα is primarily required for IL-7R+ precursor stages and partially affects small intestine ILC1 after differentiation. This study suggests that RORα promotes ILC1 differentiation while suppressing NK cell differentiation at the ILC precursor stage in the adult BM.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624951","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

Porphyromonas gingivalis outer membrane vesicles divert host innate immunity and promote inflammation via C4' monophosphorylated lipid A. 牙龈卟啉单胞菌外膜囊泡通过C4单磷酸化脂质A转移宿主先天免疫，促进炎症反应。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-12 DOI: 10.1093/jimmun/vkae050

Stephen R Coats, Thet Hnin Su, Zoe Luderman Miller, Alisa J King, Joshua Ortiz, Angel Reddy, Sarah R Alaei, Sumita Jain

{"title":"Porphyromonas gingivalis outer membrane vesicles divert host innate immunity and promote inflammation via C4' monophosphorylated lipid A.","authors":"Stephen R Coats, Thet Hnin Su, Zoe Luderman Miller, Alisa J King, Joshua Ortiz, Angel Reddy, Sarah R Alaei, Sumita Jain","doi":"10.1093/jimmun/vkae050","DOIUrl":"https://doi.org/10.1093/jimmun/vkae050","url":null,"abstract":"Porphyromonas gingivalis (Pg) is a prevalent pathogen that promotes human periodontal disease (PD) and exacerbates systemic comorbidities such as atherosclerosis, rheumatoid arthritis, and Alzheimer's disease. Pg produces nonphosphorylated tetra-acylated lipid A (NPLA) in its outer membrane (OM) that evades host Toll-like receptor 4 (TLR4), inflammasome pathways, and cationic peptides, enhancing bacterial survival. Here, we show that Pg also releases outer membrane vesicles (OMVs) that engage and divert host cell TLR4, inflammasome, and LL-37 responses away from the microbe. We determined that Pg OMVs are enriched for C4' monophosphoryl lipid A (C4'-MPLA), an established agonist for TLR4-TRIF-IFNβ and inflammasome-IL-1β responses. Comparisons of Pg 381 and Pg 33277 stationary phase cultures revealed higher OMV production by Pg 381, which correlates with its higher proinflammatory pathogenicity. The cationic peptide, polymyxin B (PMB), which selectively binds lipid A C4'-phosphate, reduces OMV-stimulated HEK cell TLR4 activation and THP-1 cell IL-1β production, confirming the proinflammatory role for OMV-C4'-MPLA. Similar to PMB, the host defense peptide, LL-37, inhibits OMV-C4'-MPLA-dependent HEK cell TLR4 activation. PMB and LL-37 also blocked OMV-C4'-MPLA-driven TLR4 activation in human umbilical vein endothelial cells. Finally, wild-type Pg-containing OM-NPLA is highly resistant to LL-37 antimicrobial activity, whereas the ΔlpxF mutant bacterium, retaining OM-C4'-MPLA, is killed by the peptide. In summary, Pg escapes host TLR4 signaling, inflammasome activation, and LL-37 interaction by retaining immunoevasive OM-NPLA. Moreover, Pg dispenses proinflammatory OMV-C4'-MPLA, which engages and redirects those host defenses. We suggest that OMV-C4'-MPLA triggers elevated IFNβ and IL-1β cytokines, which typify PD comorbidities, and drive PD-related alveolar bone loss.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710267","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

EZH2 coordinates memory B-cell programming and recall responses. EZH2协调记忆b细胞编程和回忆反应。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-12 DOI: 10.1093/jimmun/vkaf004

Keenan J Wiggins, Mark E Williams, Sakeenah L Hicks, Herbey O Padilla-Quirarte, Jobaida Akther, Troy D Randall, Jeremy M Boss, Christopher D Scharer

{"title":"EZH2 coordinates memory B-cell programming and recall responses.","authors":"Keenan J Wiggins, Mark E Williams, Sakeenah L Hicks, Herbey O Padilla-Quirarte, Jobaida Akther, Troy D Randall, Jeremy M Boss, Christopher D Scharer","doi":"10.1093/jimmun/vkaf004","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf004","url":null,"abstract":"Antigen-experienced memory B-cells (MBC) are endowed with enhanced functional properties compared to naïve B cells and play an important role in the humoral response. However, the epigenetic enzymes and programs that govern their rapid differentiation are incompletely understood. Here, the role of the histone H3 lysine 27 methyltransferase EZH2 in the formation of MBC in response to an influenza infection was determined in Mus musculus. EZH2 was expressed in all postactivated B-cell subsets, including MBC and antibody-secreting cells (ASC), with maximal expression in germinal center (GC) B cells. Deletion of EZH2 resulted in a skewing of the MBC pool towards a non-GC, IgM+ MBC subset that failed to fully express CCR6 and CD73 at both early and late infection time points. Intriguingly, although EZH2 protein levels were reduced in knockout MBC, deletion was not fully efficient, indicating a strong selective pressure to maintain EZH2 methyltransferase activity. Single-cell RNA-seq of antigen-specific MBC identified a core set of upregulated genes that are likely EZH2 targets across MBC subsets. Finally, defects in the ability to form secondary ASC and GC cells in response to a lethal challenge were observed in EZH2-deficient mice, indicating significant functional impairment in the absence of EZH2. These data show that EZH2 is a critical epigenetic modulator of MBC differentiation and functional potential during reactivation.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615588","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

Discovery of a new anti-γc antibody in clinical development for the treatment of autoimmune diseases. 发现一种新的抗γ - c抗体用于治疗自身免疫性疾病的临床开发。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-12 DOI: 10.1093/jimmun/vkae020

Chin Wai Hui, Wai Chung Wu, Tak Keung Tong, Carol Shiu, Hoi Lam Ng, Shui On Leung

{"title":"Discovery of a new anti-γc antibody in clinical development for the treatment of autoimmune diseases.","authors":"Chin Wai Hui, Wai Chung Wu, Tak Keung Tong, Carol Shiu, Hoi Lam Ng, Shui On Leung","doi":"10.1093/jimmun/vkae020","DOIUrl":"https://doi.org/10.1093/jimmun/vkae020","url":null,"abstract":"Autoimmune disease refers to a condition when the immune system anomalously attacks its own body and healthy cells. Although the exact causes of autoimmune diseases are unknown, it is recognized that excessive or aberrant cytokine responses contribute significantly to the development of autoimmunity. Among them, the common gamma c chain (γc) cytokines driven signaling cascade plays an indispensable role in driving pathogenic immune responses in patients with autoimmune diseases. Thus, we hypothesize that the development of an antibody targeting γc receptor could serve as a potential approach for treating autoimmune diseases and fulfil the unmet medical needs in this area. Here, we demonstrate that a humanized anti-γc antibody, hC2, could show high binding affinity to the human γc receptor and suppress 6 γc cytokines (interleukin [IL]-2, IL-4, IL-7, IL-9, IL-15 and IL-21)-driven STAT phosphorylation, leading to inhibition of autoimmunity and activation in B, T, and natural killer cell lines. Similar inhibitory effects were observed in the human peripheral blood mononuclear cell culture. Moreover, administration of hC2 could reduce expansion and tissue infiltration of T helper and cytotoxic T cells, leading to attenuation of damages to skin, liver, and kidney in the humanized xenograft mouse model. The current study demonstrates the potential of γc blockades for the treatment of T cell-mediated autoimmune diseases and chronic graft-versus-host disease. Anti-γc antibody hC2 might offer a more efficacious therapy compared with antibodies targeting a single γc cytokine and safer therapy than JAK inhibitors to fulfill the unmet medical needs in the autoimmune diseases in the future.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753029","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

Novel RORγt inverse agonists limit IL-17-mediated liver inflammation and fibrosis. 新型rorr γt逆激动剂限制il -17介导的肝脏炎症和纤维化。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-11 DOI: 10.1093/jimmun/vkaf014

Afrooz Dabbaghizadeh, Jessica Dion, Yousef Maali, Ahmed Fouda, Nathalie Bédard, Gertruda Evaristo, Ghada S Hassan, Jean Tchervenkov, Naglaa H Shoukry

{"title":"Novel RORγt inverse agonists limit IL-17-mediated liver inflammation and fibrosis.","authors":"Afrooz Dabbaghizadeh, Jessica Dion, Yousef Maali, Ahmed Fouda, Nathalie Bédard, Gertruda Evaristo, Ghada S Hassan, Jean Tchervenkov, Naglaa H Shoukry","doi":"10.1093/jimmun/vkaf014","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf014","url":null,"abstract":"Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by RORγt and produced by Th17 CD4+ and γδ-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel RORγt inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL/6 mice received 2 weekly injections of CCl4 for 4 weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P < 0.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and γδ-T cells, P < 0.05), and myeloid (CD11b+) cells (P = 0.04), most significantly eosinophils (P < 0.05). Furthermore, IL-17A production by CD4+ and γδ-T cells was diminished (P < 0.05 and P < 0. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and ɑ-smooth muscle actin [ɑ-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgfβ) (P < 0.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615701","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

Regulation of IL-17A-mediated hypersensitivity by extracellular vesicles and lipid nanoparticles carrying miR-451a. 携带miR-451a的细胞外囊泡和脂质纳米颗粒调节il - 17a介导的超敏反应。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-11 DOI: 10.1093/jimmun/vkae049

Takanobu Yoshida, Ken Takashima, Yohana S Mtali, Yusuke Miyashita, Asuka Iwamoto, Yoshimi Fukushima, Kimitoshi Nakamura, Hiroyuki Oshiumi

{"title":"Regulation of IL-17A-mediated hypersensitivity by extracellular vesicles and lipid nanoparticles carrying miR-451a.","authors":"Takanobu Yoshida, Ken Takashima, Yohana S Mtali, Yusuke Miyashita, Asuka Iwamoto, Yoshimi Fukushima, Kimitoshi Nakamura, Hiroyuki Oshiumi","doi":"10.1093/jimmun/vkae049","DOIUrl":"https://doi.org/10.1093/jimmun/vkae049","url":null,"abstract":"Extracellular vesicles (EVs), including exosomes, mediate intercellular communication by transporting functional molecules between donor cells and recipient cells, thereby regulating biological processes, such as immune responses. miR-451a, an immune regulatory microRNA, is highly abundant in circulating EVs; however, its precise physiological significance remains to be fully elucidated. Here, we demonstrate that miR-451a deficiency exacerbates delayed-type hypersensitivity (DTH) in mice. Notably, miR-451a knockout resulted in a significant increase in the number of interleukin (IL)-17A-expressing T helper 17 and γδ T cells infiltrating DTH-induced ear lesions. miR-451a deficiency also increased the number of γδ T cells in the secondary lymphoid tissues. Comprehensive analyses revealed that miR-451 deficiency promoted the expression of Rorc and γδ T cell-related genes following sensitization with allergens. Moreover, intravenous administration of wild-type EVs to miR-451a knockout mice increased cellular miR-451a levels in tissues and significantly attenuated the severity of DTH. Furthermore, synthetic lipid nanoparticles encapsulating miR-451a effectively mitigated DTH. Our findings indicate the importance of circulating miR-451a in the proliferation of γδ T cells and highlight the therapeutic potential of lipid nanoparticle-based microRNA delivery platforms for interventions in immune-related diseases.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615730","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

Fish requires FasL to facilitate CD8+ T-cell function and antimicrobial immunity. 鱼类需要FasL促进CD8+ t细胞功能和抗微生物免疫。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-10 DOI: 10.1093/jimmun/vkaf022

Kang Li, Yating Zhu, Zhichao Fang, Ming Geng, Jiansong Zhang, Yuying Zheng, Yi Cao, Xiumei Wei, Jialong Yang

{"title":"Fish requires FasL to facilitate CD8+ T-cell function and antimicrobial immunity.","authors":"Kang Li, Yating Zhu, Zhichao Fang, Ming Geng, Jiansong Zhang, Yuying Zheng, Yi Cao, Xiumei Wei, Jialong Yang","doi":"10.1093/jimmun/vkaf022","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf022","url":null,"abstract":"Although bony fish have CD8+ T cells, the mechanisms by which these early-evolved cytotoxic cells combat intracellular pathogens remain unclear. In the present study, using Nile tilapia as a model, we investigated the detailed function, mechanism, and evolutionary pattern concerning CD8+ T cells. By depleting CD8+ T cells, they are found essential in combating Edwardsiella piscicida infection. Using siRNA interference, we propose that unlike the strategy predominantly relying on perforin/granzyme in mammals, CD8+ T-cell effector function is mediated by both FasL and perforin/granzyme in fish. Upon E. piscicida infection, FasL is induced to express in CD8+ T cells; both recombinant FasL and adoptively transferred FasL+CD8+ T cells facilitate the apoptosis of target cells. Meanwhile, tilapia FasL also triggers the apoptosis of T cells to archive homeostasis. Since advances in mammals highlight the indispensable role of FasL in maintaining CD8+ T-cell homeostasis, rather than in effector function or anti-infective immunity, we therefore propose the unique dual function of FasL in executing effector function and maintaining homeostasis in fish. Mechanistically, tilapia T cells utilize mTORC1/c-Myc axis to regulate pathogen-induced FasL expression, which binds to Fas and activates caspase-8/caspase-3 pathway, mediating apoptosis in target cells and T cells themselves. This represents a novel mechanism underpinning CD8+ T-cell function in fish. Our findings demonstrate that CD8+ T cells reshaped the FasL-dependent strategy throughout evolution, thereby enhancing the precision and specificity of adaptive immunity.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615598","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

SYK negatively regulates ITAM-mediated human NK cell signaling and CD19-CAR NK cell efficacy. SYK负调控itam介导的人NK细胞信号传导和CD19-CAR NK细胞的功效。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-09 DOI: 10.1093/jimmun/vkaf012

Alberto J Millan, Vincent Allain, Indrani Nayak, Jeremy B Libang, Lilian M Quijada-Madrid, Janice S Arakawa-Hoyt, Gabriella Ureno, Allison Grace Rothrock, Avishai Shemesh, Oscar A Aguilar, Justin Eyquem, Jayajit Das, Lewis L Lanier

{"title":"SYK negatively regulates ITAM-mediated human NK cell signaling and CD19-CAR NK cell efficacy.","authors":"Alberto J Millan, Vincent Allain, Indrani Nayak, Jeremy B Libang, Lilian M Quijada-Madrid, Janice S Arakawa-Hoyt, Gabriella Ureno, Allison Grace Rothrock, Avishai Shemesh, Oscar A Aguilar, Justin Eyquem, Jayajit Das, Lewis L Lanier","doi":"10.1093/jimmun/vkaf012","DOIUrl":"10.1093/jimmun/vkaf012","url":null,"abstract":"Natural killer (NK) cells express activating receptors that signal through ITAM (immunoreceptor tyrosine-based activation motif)-bearing adapter proteins. The phosphorylation of each ITAM creates binding sites for SYK and ZAP70 protein tyrosine kinases to propagate downstream signaling including the induction of Ca2+ influx. While all immature and mature human NK cells coexpress SYK and ZAP70, clonally driven memory or adaptive NK cells can methylate SYK genes, and signaling is mediated exclusively using ZAP70. Here, we examined the role of SYK and ZAP70 in a clonal human NK cell line KHYG1 by CRISPR-based deletion using a combination of experiments and mechanistic computational modeling. Elimination of SYK resulted in more robust Ca2+ influx after crosslinking of the CD16 and NKp30 receptors and enhanced phosphorylation of downstream proteins, whereas ZAP70 deletion diminished these responses. By contrast, ZAP70 depletion increased proliferation of the NK cells. As immature T cells express both SYK and ZAP70 and mature T cells often express only ZAP70, we transduced the human Jurkat cell line with SYK and found that expression of SYK increased proliferation but diminished T cell receptor-induced Ca2+ flux and activation. We performed transcriptional analysis of the matched sets of variant Jurkat and KHYG1 cells and observed profound alterations caused by SYK expression. As depletion of SYK in NK cells increased their activation, primary human NK cells were transduced with a CD19-targeting chimeric antigen receptor and were CRISPR edited to ablate SYK or ZAP70. Deletion of SYK resulted in more robust cytotoxic activity and cytokine production, providing a new therapeutic strategy of NK cell engineering for cancer immunotherapy.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615732","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

Modulation of germinal center and antibody dynamics via ipsilateral versus contralateral immunization against SARS-CoV-2. 同侧与对侧免疫对SARS-CoV-2的生发中心和抗体动力学的调节

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-09 DOI: 10.1093/jimmun/vkae067

Lauren Burmas, Wen Shi Lee, Andrew Kelly, Rosela Webster, Robyn Esterbauer, Stephen J Kent, Adam K Wheatley, Jennifer A Juno, Hyon-Xhi Tan

{"title":"Modulation of germinal center and antibody dynamics via ipsilateral versus contralateral immunization against SARS-CoV-2.","authors":"Lauren Burmas, Wen Shi Lee, Andrew Kelly, Rosela Webster, Robyn Esterbauer, Stephen J Kent, Adam K Wheatley, Jennifer A Juno, Hyon-Xhi Tan","doi":"10.1093/jimmun/vkae067","DOIUrl":"https://doi.org/10.1093/jimmun/vkae067","url":null,"abstract":"Human clinical trials have reported immunological outcomes can differ between ipsilateral (same side) and contralateral (alternate sides) prime-boost vaccination. However, our mechanistic understanding of how keeping or shifting the anatomical sites of immunization impacts the resultant germinal centers (GCs) and antibody responses is limited. Here, we use an adjuvanted SARS-CoV-2 spike vaccine to dissect GC dynamics in draining lymph nodes and serological outcomes following ipsilateral or contralateral prime-boost vaccination in C57BL/6 mice. Contralateral vaccination elicited independent GCs at distinct lymph nodes, where robust secondary GCs only appeared upon secondary distal vaccination, while ongoing GCs from the primary site were not boosted. In contrast, ipsilateral vaccination resulted in sustained GC activity. Ipsilateral vaccination accelerated the development of antibody titers against ancestral (wild-type [WT]), Beta, and BA.1 but were later comparable between ipsilateral and contralateral groups in terms of magnitude, durability, and neutralization capacity beyond 28 d. Using a heterologous SARS-CoV-2 WT/BA.1 spike prime-boost model, cross-reactive GC responses were generated against WT and BA.1 spike, with analogous serological and GC dynamics to our homologous model. Within the cross-reactive GC B cells, differential recognition of WT and BA.1 antigens was observed and were further compartmentalized in primary or secondary GCs, depending on ipsilateral or contralateral regimes. Collectively, maintaining a common prime-boost site augments the kinetics of memory B cell recall and transiently drive higher antibody titers, but longer-term serological outcomes are unaffected by the anatomical localization of immunization.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615690","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