The Journal of Immunology最新文献

Challenges in the Development of NK-92 Cells as an Effective Universal Off-the-Shelf Cellular Therapeutic. 将 NK-92 细胞开发为有效的通用现成细胞疗法所面临的挑战。

The Journal of Immunology Pub Date : 2024-09-18 DOI: 10.4049/jimmunol.2400173

Zhiyuan Niu,Mengjun Wang,Yangchun Yan,Xinru Jin,Linwei Ning,Bingqian Xu,Yanfeng Wang,Yuekai Hao,Zhixia Luo,Changjiang Guo,Lingtong Zhi,Wuling Zhu

{"title":"Challenges in the Development of NK-92 Cells as an Effective Universal Off-the-Shelf Cellular Therapeutic.","authors":"Zhiyuan Niu,Mengjun Wang,Yangchun Yan,Xinru Jin,Linwei Ning,Bingqian Xu,Yanfeng Wang,Yuekai Hao,Zhixia Luo,Changjiang Guo,Lingtong Zhi,Wuling Zhu","doi":"10.4049/jimmunol.2400173","DOIUrl":"https://doi.org/10.4049/jimmunol.2400173","url":null,"abstract":"The human-derived NK-92 cell-based CAR-NK therapy exhibits inconsistency with overall suboptimal efficacy and rapid in vivo clearance of CAR-NK92 cells in cancer patients. Analysis indicates that although pre-existing IgM in healthy individuals (n = 10) strongly recognizes both NK-92 and CAR-NK92 cells, IgG and IgE do not. However, only a subset of cancer patients (3/8) exhibit strong IgM recognition of these cells, with some (2/8) showing pre-existing IgG recognition. These results suggest a natural immunoreactivity between NK-92 and CAR-NK92 cells and pre-existing human Abs. Furthermore, the therapy's immunogenicity is evidenced by enhanced IgG and IgM recognition postinfusion of CAR-NK92 cells. We also confirmed that healthy plasma's cytotoxicity toward these cells is reduced by complement inhibitors, suggesting that Abs may facilitate the rapid clearance of CAR-NK92 cells through complement-dependent cytotoxicity. Given that NK-92 cells lack known receptors for IgG and IgM, identifying and modifying the recognition targets for these Abs on NK-92 and CAR-NK92 cells may improve clinical outcomes. Moreover, we discovered that the 72nd amino acid of the NKG2D receptor on NK-92 cells is alanine. Previous studies have demonstrated polymorphism at the 72nd amino acid of the NKG2D on human NK cells, with NKG2D72Thr exhibiting a superior activation effect on NK cells compared with NKG2D72Ala. We confirmed this conclusion also applies to NK-92 cells by in vitro cytotoxicity experiments. Therefore, reducing the immunoreactivity and immunogenicity of CAR-NK92 and directly switching NK-92 bearing NKG2D72Ala to NKG2D72Thr represent pressing challenges in realizing NK-92 cells as qualified universal off-the-shelf cellular therapeutics.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Understanding the Role of miR-29a in the Regulation of RAG1, a Gene Associated with the Development of the Immune System. 了解 miR-29a 在调节与免疫系统发育有关的基因 RAG1 中的作用。

The Journal of Immunology Pub Date : 2024-09-13 DOI: 10.4049/jimmunol.2300344

Urbi Roy,Sagar Sanjiv Desai,Susmita Kumari,Tanzeem Bushra,Bibha Choudhary,Sathees C Raghavan

{"title":"Understanding the Role of miR-29a in the Regulation of RAG1, a Gene Associated with the Development of the Immune System.","authors":"Urbi Roy,Sagar Sanjiv Desai,Susmita Kumari,Tanzeem Bushra,Bibha Choudhary,Sathees C Raghavan","doi":"10.4049/jimmunol.2300344","DOIUrl":"https://doi.org/10.4049/jimmunol.2300344","url":null,"abstract":"The process of Ag receptor diversity is initiated by RAGs consisting of RAG1 and RAG2 in developing lymphocytes. Besides its role as a sequence-specific nuclease during V(D)J recombination, RAGs can also act as a structure-specific nuclease leading to genome instability. Thus, regulation of RAG expression is essential to maintaining genome stability. Previously, the role of miR29c in the regulation of RAG1 was identified. In this article, we report the regulation of RAG1 by miR-29a in the lymphocytes of both mice (Mus musculus) and humans (Homo sapiens). The level of RAG1 could be modulated by overexpression of miR-29a and inhibition using anti-miRs. Argonaute2-immunoprecipitation and high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation studies established the association of miR-29a and RAG1 with Argonaute proteins. We observed a negative correlation between miR-29a and RAG1 levels in mouse B and T cells and leukemia patients. Overexpression of pre-miR-29a in the bone marrow cells of mice led to the generation of mature miR-29a transcripts and reduced RAG1 expression, which led to a significant reduction in V(D)J recombination in pro-B cells. Importantly, our studies are consistent with the phenotype reported in miR-29a knockout mice, which showed impaired immunity and survival defects. Finally, we show that although both miR-29c and miR-29a can regulate RAG1 at mRNA and protein levels, miR-29a substantially impacts immunity and survival. Our results reveal that the repression of RAG1 activity by miR-29a in B cells of mice and humans is essential to maintain Ig diversity and prevent hematological malignancies resulting from aberrant RAG1 expression in lymphocytes.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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N-Glycan Branching Regulates BTLA Opposite to PD-1 to Limit T Cell Hyperactivity Induced by Branching Deficiency. N-聚糖分支与 PD-1 相反调控 BTLA，以限制分支缺失诱导的 T 细胞过度活跃。

The Journal of Immunology Pub Date : 2024-09-13 DOI: 10.4049/jimmunol.2300568

Haik Mkhikian,Raymond W Zhou,Hayk Saryan,Christofer Daniel Sánchez,Aswath Balakrishnan,Justin Dang,Christie-Lynn Mortales,Michael Demetriou

{"title":"N-Glycan Branching Regulates BTLA Opposite to PD-1 to Limit T Cell Hyperactivity Induced by Branching Deficiency.","authors":"Haik Mkhikian,Raymond W Zhou,Hayk Saryan,Christofer Daniel Sánchez,Aswath Balakrishnan,Justin Dang,Christie-Lynn Mortales,Michael Demetriou","doi":"10.4049/jimmunol.2300568","DOIUrl":"https://doi.org/10.4049/jimmunol.2300568","url":null,"abstract":"N-glycan branching is a potent and multifaceted negative regulator of proinflammatory T cell and B cell function. By promoting multivalent galectin-glycoprotein lattice formation at the cell surface, branching regulates clustering and/or endocytosis of the TCR complex (TCR+CD4/CD8), CD45, CD25, BCR, TLR2 and TLR4 to inhibit T cell and B cell activation/proliferation and proinflammatory TH1 and TH17 over TH2 and induced T regulatory cell responses. In addition, branching promotes cell surface retention of the growth inhibitory receptor CTLA-4. However, the role of N-glycan branching in regulating cell surface levels of other checkpoint receptors such as BTLA (B and T lymphocyte attenuator) and PD-1 (programmed cell death protein 1) is unknown. In this study, we report that whereas branching significantly enhances PD-1 cell surface expression by reducing loss from endocytosis, the opposite occurs with BTLA in both T cells and B cells. T cell hyperactivity induced by branching deficiency was opposed by BTLA ligation proportional to increased BTLA expression. Other members of the BTLA/HVEM (herpesvirus entry mediator) signaling axis in T cells, including HVEM, LIGHT, and CD160, are largely unaltered by branching. Thus, branching-mediated endocytosis of BTLA is opposite of branching-induced inhibition of PD-1 endocytosis. In this manner, branching deficiency-induced upregulation of BTLA appears to serve as a checkpoint to limit extreme T cell hyperactivity and proinflammatory outcomes in T cells with low branching.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Immune Response to SARS-CoV-2 in Vaccine-naive Pregnant Women: Assessment of IgG and IgA Antibody Profile at Delivery and 42 Days Postpartum. 未接种疫苗的孕妇对 SARS-CoV-2 的免疫反应：评估分娩时和产后 42 天的 IgG 和 IgA 抗体谱。

The Journal of Immunology Pub Date : 2024-09-11 DOI: 10.4049/jimmunol.2400055

Mirjam Druškovič,Miha Lučovnik,Vita Andreja Mesarič,Gorazd Kavšek,Marijana Vidmar Šimic,Andreja Trojner Bregar,Tatjana Avšič Županc,Alojz Ihan,Tanja Premru Sršen

{"title":"Immune Response to SARS-CoV-2 in Vaccine-naive Pregnant Women: Assessment of IgG and IgA Antibody Profile at Delivery and 42 Days Postpartum.","authors":"Mirjam Druškovič,Miha Lučovnik,Vita Andreja Mesarič,Gorazd Kavšek,Marijana Vidmar Šimic,Andreja Trojner Bregar,Tatjana Avšič Županc,Alojz Ihan,Tanja Premru Sršen","doi":"10.4049/jimmunol.2400055","DOIUrl":"https://doi.org/10.4049/jimmunol.2400055","url":null,"abstract":"This prospective cohort study assessed the SARS-CoV-2 IgG and IgA Ab profiles at delivery and 42 d postpartum in unvaccinated SARS-CoV-2-positive pregnant women and determined the association with the timing and the clinical course of the infection. A total of 387 vaccine-naive women with confirmed SARS-CoV-2 infection during pregnancy were included. IgG and IgA Abs were detected in maternal blood at delivery and 42 d postpartum using ELISA kits. The relationships between Ab detection and value and clinical features, including the timing of the infection, were analyzed using univariate and multivariate logistic and linear regression models. The mean gestational age at infection was 31 4/7 wk of pregnancy. Symptoms of SARS-CoV-2 infection were present in 88.1% of women. IgG and IgA Abs were detected in 45.7 and 58.9% at delivery, respectively, increasing to 72.7 and 76.8% at 42 d postpartum. Detection of IgG and IgA Abs in maternal blood at delivery was independently associated with symptomatic infection (adjusted odds ratio [OR] 3.13, 95% confidence interval (CI): 1.47-6.69 and adjusted OR 3.62, 95% CI: 1.8-7.26, respectively), but not with the time from positive swab to delivery or gestational age at positive swab. Detection of Abs at 42 d postpartum was also strongly associated with the detection of Abs at delivery (OR 29.97, 95% CI: 10.11-88.82 for IgG and OR 13.09, 95% CI: 6.37-26.9 for IgA). Vaccine-naive pregnant women exhibit a significant and durable immune response to SARS-CoV-2, which is more pronounced in symptomatic women but independent of gestational age at diagnosis or the diagnosis-to-delivery interval.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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The Journal of Immunology Pub Date : 2024-01-01 DOI: 10.4049/jimmunol.2390022

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The CATERPILLERS CATERPILLERS

The Journal of Immunology Pub Date : 2024-01-01 DOI: 10.4049/jimmunol.2300709

Amal O. Amer

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Dynamic MAIT Cell Recovery after Severe COVID-19 Is Transient with Signs of Heterogeneous Functional Anomalies 严重 COVID-19 后 MAIT 细胞的动态恢复是短暂的，并伴有异质性功能异常的迹象

The Journal of Immunology Pub Date : 2023-12-20 DOI: 10.4049/jimmunol.2300639

Tobias Kammann, Jean-Baptiste Gorin, Tiphaine Parrot, Yu Gao, Andrea Ponzetta, Johanna Emgård, Kimia T. Maleki, Takuya Sekine, Olga Rivera-Ballesteros, Sara Gredmark-Russ, Olav Rooyackers, Magdalena Skagerberg, Lars I. Eriksson, Anna Norrby-Teglund, Jeffrey Y.W. Mak, David P. Fairlie, Niklas K. Björkström, Jonas Klingström, Hans-Gustaf Ljunggren, Soo Aleman, Marcus Buggert, Kristoffer Strålin, Johan K. Sandberg

{"title":"Dynamic MAIT Cell Recovery after Severe COVID-19 Is Transient with Signs of Heterogeneous Functional Anomalies","authors":"Tobias Kammann, Jean-Baptiste Gorin, Tiphaine Parrot, Yu Gao, Andrea Ponzetta, Johanna Emgård, Kimia T. Maleki, Takuya Sekine, Olga Rivera-Ballesteros, Sara Gredmark-Russ, Olav Rooyackers, Magdalena Skagerberg, Lars I. Eriksson, Anna Norrby-Teglund, Jeffrey Y.W. Mak, David P. Fairlie, Niklas K. Björkström, Jonas Klingström, Hans-Gustaf Ljunggren, Soo Aleman, Marcus Buggert, Kristoffer Strålin, Johan K. Sandberg","doi":"10.4049/jimmunol.2300639","DOIUrl":"https://doi.org/10.4049/jimmunol.2300639","url":null,"abstract":"Abstract Mucosal-associated invariant T (MAIT) cells are an abundant population of unconventional T cells in humans and play important roles in immune defense against microbial infections. Severe COVID-19 is associated with strong activation of MAIT cells and loss of these cells from circulation. In the present study, we investigated the capacity of MAIT cells to recover after severe COVID-19. In longitudinal paired analysis, MAIT cells initially rebounded numerically and phenotypically in most patients at 4 mo postrelease from the hospital. However, the rebounding MAIT cells displayed signs of persistent activation with elevated expression of CD69, CD38, and HLA-DR. Although MAIT cell function was restored in many patients, a subgroup displayed a predominantly PD-1high functionally impaired MAIT cell pool. This profile was associated with poor expression of IFN-γ and granzyme B in response to IL-12+IL-18 and low levels of polyfunctionality. Unexpectedly, although the overall T cell counts recovered, normalization of the MAIT cell pool failed at 9-mo follow-up, with a clear decline in MAIT cell numbers and a further increase in PD-1 levels. Together, these results indicate an initial transient period of inconsistent recovery of MAIT cells that is not sustained and eventually fails. Persisting MAIT cell impairment in previously hospitalized patients with COVID-19 may have consequences for antimicrobial immunity and inflammation and could potentially contribute to post-COVID-19 health problems.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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A Bacterial and Ganglioside-based Nanoparticle Initiates Reprogramming of Macrophages and Promotes Antitumor Phenotypes 一种基于细菌和神经节苷脂的纳米粒子可启动巨噬细胞重编程并促进抗肿瘤表型

The Journal of Immunology Pub Date : 2023-12-20 DOI: 10.4049/jimmunol.2300256

Rydell Alvarez-Arzola, Liliana Oliver, Michelle M. Messmer, Danielle Y.F. Twum, Kelvin P. Lee, Jason B. Muhitch, Circe Mesa, Scott I. Abrams

{"title":"A Bacterial and Ganglioside-based Nanoparticle Initiates Reprogramming of Macrophages and Promotes Antitumor Phenotypes","authors":"Rydell Alvarez-Arzola, Liliana Oliver, Michelle M. Messmer, Danielle Y.F. Twum, Kelvin P. Lee, Jason B. Muhitch, Circe Mesa, Scott I. Abrams","doi":"10.4049/jimmunol.2300256","DOIUrl":"https://doi.org/10.4049/jimmunol.2300256","url":null,"abstract":"Abstract Macrophages represent the most abundant immune component of the tumor microenvironment and often exhibit protumorigenic (M2-like) phenotypes that contribute to disease progression. Despite their generally accepted protumorigenic role, macrophages can also display tumoricidal (or M1-like) behavior, revealing that macrophages can be functionally reprogrammed, depending on the cues received within the tumor microenvironment. Moreover, such plasticity may be achieved by pharmacologic or biologic interventions. To that end, we previously demonstrated that a novel immunomodulator termed the “very small size particle” (VSSP) facilitates maturation of dendritic cells and differentiation of myeloid-derived suppressor cells to APCs with reduced suppressive activity in cancer models. VSSP was further shown to act in the bone marrow to drive the differentiation of progenitors toward monocytes, macrophages, and dendritic cells during emergency myelopoiesis. However, the underlying mechanisms for VSSP-driven alterations in myeloid differentiation and function remained unclear. In this study, in mouse models, we focused on macrophages and tested the hypothesis that VSSP drives macrophages toward M1-like functional states via IRF8- and PU.1-dependent mechanisms. We further hypothesized that such VSSP-mediated actions would be accompanied by enhanced antitumor responses. Overall, we showed that (1) VSSP drives naive or M2-derived macrophages to M1-like states, (2) the M1-like state induced by VSSP occurs via IRF8- and PU.1-dependent mechanisms, and (3) single-agent VSSP induces an antitumor response that is accompanied by alterations in the intratumoral myeloid compartment. These results provide a deeper mechanistic underpinning of VSSP and strengthen its use to drive M1-like responses in host defense, including cancer.","PeriodicalId":22698,"journal":{"name":"The Journal of Immunology","volume":"248 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138823789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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