Journal of immunology最新文献

{"title":"MEF2D regulates T-cell function via CD70-CD27 signaling and promotes immune evasion in hepatocellular carcinoma.","authors":"Fanhua Kong, Liqing Wang, Zhongshan Lu, Jiakang Zhou, Qifa Ye, Wayne W Hancock, Yan Xiong","doi":"10.1093/jimmun/vkaf228","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf228","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) stands as one of the most prevalent and fatal malignancies globally, posing a persistent challenge in its treatment due to immune evasion. We knocked down MEF2D in HCC cell lines and analyzed HCC tissues and cell lines by RNA sequencing, Western blot, and immunohistochemistry. Chromatin immunoprecipitation was used to analyze the regulation of CD70 transcription by MEF2D. HCC cells with or without MEF2D knockout were injected into the livers of syngeneic BALB/c mice. Flow cytometry was used to analyze the function of T cells in tumors, spleens, and lymph nodes. We found that in contrast to wild-type tumors in immunocompetent mice, HCC with MEF2D knockdown had smaller tumors, increased T-cell activation, and impaired T regulatory (Treg) cell suppressive function. Mechanistically, MEF2D bound to the promoter region of CD70 gene and activated its transcription and this process was further enhanced by p300-induced MEF2D acetylation. CD70 blocking antibody inhibited activation of the CD70-CD27 signaling axis in murine HCC tumors, leading to impaired immunosuppressive function of Tregs and enhanced antitumor immunity. MEF2D blocks T-cell-mediated antitumor immunity by regulating the expression of CD70 and activating the CD70-CD27 signaling axis. Strategies to manipulate this pathway may improve the efficacy of liver cancer immunotherapy.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186075","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}

{"title":"H3K9 acetylation-NF-κB-AP-1 nexus targeted by ITE limits TNF-α-induced MMP-9 expression in monocytic cells.","authors":"Fatemah Bahman, Shihab Kochumon, Md Zubbair Malik, Nadeem Akther, Sindhu Jacob, Hana Drobiova, Fahd Al-Mulla, Rasheed Ahmad","doi":"10.1093/jimmun/vkaf240","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf240","url":null,"abstract":"<p><p>Matrix metalloproteinase 9 (MMP-9) plays a key role in the pathogenesis of inflammatory diseases and is upregulated by TNF-α. ITE (2-[1'H-indole-3'-carbonyl]-thiazole-4-carboxylic acid methyl ester) functions as an endogenous ligand for the aryl hydrocarbon receptor and is involved in inflammation. It is still uncertain whether ITE could affect TNF-α-induced MMP-9 expression in monocytic cells. In this study, we explored the effect of ITE on TNF-α-induced MMP-9 expression and the underlying mechanisms involved. Our results show that pretreatment of THP-1 monocytic cells with ITE significantly blocked TNF-α-induced MMP-9 expression at both the mRNA and protein secretion levels. Similar results were seen in primary human monocytes. The inhibition of MMP-9 by ITE occurs independently of TNFR1/2 modulation and apoptotic processes. RNA transcription data revealed that ITE suppresses the genes associated with inflammatory pathways. Mechanistically, histone modification profiling identified H3K9 acetylation as an epigenetic regulatory mark of TNF-α-induced MMP-9 expression. ChIP-qPCR data revealed that ITE pretreatment decreased TNF-α-triggered transcriptionally permissive acetylation marks at H3K9 in the MMP-9 promoter. Pharmacological inhibition of histone acetylation mimics the action of ITE in suppressing TNF-α-induced MMP-9 gene expression. Conversely, the acetylation induced by trichostatin A effectively reverses the inhibitory action of ITE. Moreover, increased TNF-α-induced binding of NF-κB or AP-1 at the MMP-9 promoter region was inhibited by ITE, resulting in suppression of MMP-9 gene expression. In conclusion, our study demonstrates that ITE reduces the TNF-α-induced MMP-9 expression via the H3K9 acetylation/NF-κB/AP-1 axis, highlighting a potential mechanism for mitigating MMP-9-related inflammatory disorders.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181930","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}

{"title":"Foreign epitope-specific regulatory T cells respond robustly to vaccination and limit Th1 differentiation by conventional T cells specific for the same epitope.","authors":"Peter D Krueger, Kevin C Osum, Brian T Fife, Marc K Jenkins","doi":"10.1093/jimmun/vkaf254","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf254","url":null,"abstract":"<p><p>Foxp3+ regulatory T (Treg) cells with antigen receptors (TCRs) specific for host peptides suppress autoimmunity. Paradoxically, Treg cells are also found in CD4+ T-cell populations specific for foreign (nonhost) peptides. We investigated the origin and function of these Treg cells in mice. Populations of foreign peptide-specific naïve CD4+ T cells contained Foxp3- conventional (Tconv) and Foxp3+ Treg cells in about a 90:10 ratio. Both types of T cells proliferated in parallel after vaccination with the foreign peptide in incomplete or complete Fruend's adjuvants and formed memory cells. The Tconv population failed to express Foxp3, and formed Th1, Th17, and T follicular helper cells, whereas the Treg population largely retained Foxp3, and formed Th1- and Th17-like cells. The Treg cells specific for a foreign peptide had no effect on the proliferation of Tconv cells specific for that peptide but partially reduced Th1 cells in that population. Thus, foreign epitope-specific naïve Treg cells fine-tune the primary response of Tconv cells specific for the same epitope by curbing the Th1 fate while allowing a robust response.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181919","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}

{"title":"Efficient expansion of tumor-infiltrating lymphocytes from gynecologic cancer.","authors":"Tetsuya Matsukawa, Tsunenori Ouchida, Taeko Hayakawa, Toshiaki Yoshikawa, Yusuke Ito, Hitomi Kasuya, Chisato Umehara, Satoshi Inoue, Tatsuyuki Chiyoda, Hiroshi Nishio, Wataru Yamagami, Waki Hosoda, Shiro Suzuki, Yuki Kagoya","doi":"10.1093/jimmun/vkaf259","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf259","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive immunotherapy potentially applicable to many types of solid tumors. Although gynecologic malignancies are promising targets for TIL therapy, its objective efficacy has not been established. Current TIL culture typically involves incubation of dissociated samples with high-dose IL-2 (HD-IL2) for weeks to enrich tumor-reactive T cells. While this protocol has been successfully used for melanoma TIL, it has not necessarily been optimized for other cancers. Here we investigated the method of efficiently expanding TILs derived from patients with gynecological cancers. TILs were incubated with HD-IL2 (HD-IL2-TILs) or stimulated with K562 cells expressing anti-CD3 mAb and CD80 (αCD3/CD80-TILs). We found that the αCD3/CD80-TILs showed significantly better proliferation than HD-IL2-TILs. The TIL populations that predominantly expanded upon αCD3/CD80 stimulation expressed high levels of PD-1 and CD28. CD28 co-stimulation was essential to overcome PD-1-mediated signals for growth suppression. We also identified DUSP4 as a negative regulator of TIL proliferation by downregulating ERK phosphorylation. The αCD3/CD80-TILs were reactive to tumor cells as shown by IFN-γ secretion and CD107a expression. Moreover, the αCD3/CD80-TILs were efficiently transduced with a chimeric cytokine receptor that we had previously developed to provide constitutive IL-7 signaling, resulting in superior in vivo persistence and antitumor effects without exogenous cytokine support in mouse models. Collectively, this study shows that direct stimulation of TILs with anti-CD3 mAb and CD28 co-stimulation achieves efficient expansion of tumor-reactive TILs. Genetic engineering of cytokine signaling in TILs may further enhance TIL functions and replace cytokine administration after TIL infusion.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149520","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}

{"title":"NR4A nuclear receptor expression in human macrophages mediates apoptosis and controls Mycobacterium tuberculosis growth.","authors":"Jan D Simper, Natalie Jarvis, Susanta Pahari, Daniella Ortega, Abul Azad, Stephen Safe, Eusondia Arnett, Larry S Schlesinger","doi":"10.1093/jimmun/vkaf252","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf252","url":null,"abstract":"<p><p>Tuberculosis (TB), a significant global health issue, needs novel therapeutic approaches to reduce its burden. Studying host-pathogen interactions provides new targets for host-directed therapeutics (HDTs). Nuclear receptors (NRs) are important master regulators of cellular function and bona fide drug targets. Herein, we identify high basal expression of the NR4A NR family in human alveolar macrophages and determine that all 3 members (NR4A1, NR4A2, and NR4A3) are upregulated in response to Mycobacterium tuberculosis (M.tb) infection. NR4A expression was also increased in our recently developed human alveolar macrophage-like (AML) cell model compared to monocyte-derived macrophages. We investigated the role of the NR4As in apoptosis given its importance in controlling M.tb growth. NR4A small interfering RNA knockdown in AML cells prior to their treatment with apoptosis-inducing compounds resulted in reduced caspase-3/7 activity, indicating reduced apoptosis. Additionally, knockdown prior to M.tb infection resulted in reduced apoptosis of AML cells and increased M.tb growth. Treatment of AML cells with NR4A ligands significantly reduced M.tb growth while treatment with an NR4A antagonist significantly increased it. In conclusion, we identify the expression, location, and apoptotic activity of NR4A NRs in human macrophages and their potential as new TB HDT therapeutic targets.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176099","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}

{"title":"The B cell subtypes and VDJ repertoire of young adult rhesus macaques.","authors":"Andy Kwan Pui Chan, Diane E Griffin","doi":"10.1093/jimmun/vkaf212","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf212","url":null,"abstract":"<p><p>Rhesus macaques (RMs) are widely employed as a preclinical model in vaccination and infectious disease studies, yet their B cell immunobiology and immunogenetics remain ill-characterized. In this study, single-cell RNA/VDJ sequencing was conducted on peripheral blood mononuclear cell samples from 6 RMs to describe the transcriptomic and V(D)JC repertoires of B cells and subtypes. Twelve RM B cell clusters of distinct transcriptional states were identified, including IgM+ memory B cells (MBCs), class-switched MBCs, CD11c+ MBCs, and activated B cells. Novel gene signatures were also characterized for each B cell subtype, such as FCRL2 and CD24 for circulating marginal zone-like B cells. In addition, VDJ repertoire properties of the global B cell population and each B cell subtype were elucidated, including IGH/K/L-V(D)JC gene family and subtype usage, class-switch recombination status, somatic hypermutation rate and levels, CDRH3 amino acid length, and CDRH3 amino acid hydrophobicity scores. Interesting insights included the 1:1 ratio of kappa and lambda light chain usage and a preferential decreased IGHV3 but increased IGHV1 and 5 gene family usage in IGHG1 than IGHM-bearing B cells. Altogether, this study through comprehensive transcriptomic analyses identifies 12 distinct RM B cell subtypes paired with their respective V(D)JC repertoire, unraveling the complexity of B cell heterogeneity and improving future preclinical studies that can translate insights from this important nonhuman primate model to the understanding of human immunobiology.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149510","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}

{"title":"Protective efficacy of bivalent anti-flagellin IgY against Pseudomonas aeruginosa infection in acute pneumonia and burn wound murine models.","authors":"Tooba Sadat Ahmadi, Seyed Latif Mousavi Gargari","doi":"10.1093/jimmun/vkaf237","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf237","url":null,"abstract":"<p><p>The rising emergence of antimicrobial-resistant Pseudomonas aeruginosa strains necessitates effective therapeutic strategies like antibody-based immunotherapy. Flagellin is crucial in P. aeruginosa infection development. This study evaluated the antibacterial efficacy of bivalent immunoglobulin Y (IgY) raised against both A and B flagellins. IgY's immunoreactivity and specificity were examined via ELISA and immunoblot analysis. Functional assays, including motility, biofilm formation, and opsonophagocytic tests, examined the antibody's inhibitory effects on diverse bacterial functions. Murine models of acute pneumonia and burn wounds, using both standard and nosocomial strains, were employed to assess in vivo protection. Anti-FlaAB IgY exhibited higher immunoreactivity and specificity against PAO1 (FlaB+) than PAK (FlaA+). The bivalent antibody demonstrated admissible potency compared to previously characterized monovalent IgYs under similar conditions. Passive immunotherapy provided 100% and 40% protection in burned mice infected with standard and nosocomial strains, respectively, and ensured 100% protection in an acute pneumonia model. Although both anti-FlaB and anti-FlaAB IgYs showed similar efficacy in vivo, certain in vitro assays revealed that monovalent antibodies had reduced activity against heterologous strain at the lowest examined concentrations. Considering potential fluctuations in antibody concentration and the need for broad coverage against both flagellin types, the bivalent formulation emerges as a more optimal and flexible choice for passive immunotherapy in burn wound infections.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137852","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}

{"title":"Glucagon-like peptide-1 receptor signaling deficiency exacerbates hematopoietic stem cell graft rejection in mice.","authors":"Mark Rusznak, Daniela Sierra-Hernandez, Catherine Dupuy, Shinji Toki, Ashley Y Wu, Uttam Rao, Masako Abney, Jian Zhang, Qianni Hu, Christian M Warren, Daniel J Drucker, Kevin D Niswender, Brian Engelhardt, Tae Kon Kim, Katherine N Gibson-Corley, Katherine N Cahill, Kenneth R Cooke, R Stokes Peebles","doi":"10.1093/jimmun/vkaf251","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf251","url":null,"abstract":"<p><p>Graft failure (GF) following hematopoietic stem cell transplantation (HSCT) remains a major complication particularly in the setting of human leukocyte antigen (HLA)-mismatched grafts where residual host lymphocytes can drive immune-mediated rejection. While strategies to mitigate GF have been explored, such as intensified conditioning or donor T cell supplementation, these approaches carry significant risks, including increased toxicity and graft-versus-host disease (GVHD). Recent studies have highlighted the glucagon-like peptide-1 receptor (GLP1R) as a critical regulator of immune homeostasis, yet its role in HSC engraftment remains unexplored. Here, we demonstrated that GLP1R deficiency in recipient mice leads to a profound increase in GF following MHC-mismatched allogeneic HSCT. Although GLP1R knockout (GLP1RKO) and wild-type (WT) mice exhibited comparable survival and engraftment following syngeneic or minor antigen-mismatched transplants, GLP1RKO mice undergoing MHC-mismatched HSCT experienced significantly greater weight loss, earlier mortality, and reduced donor chimerism. Histologic and cytokine analyses confirmed that this phenotype is not driven by GVHD, but rather by early graft rejection. Depletion of CD90+ recipient T cells prior to transplantation rescued engraftment in GLP1RKO mice, further supporting a model in which GLP1R signaling restrains host lymphocyte-mediated graft rejection. These findings identify GLP1R as a novel regulator of allogeneic HSC engraftment and suggest that GLP1R agonists, widely used for metabolic disorders, may have therapeutic potential in preventing HSC graft rejection. Given the lack of targeted interventions for HSC graft rejection, further studies are warranted to investigate GLP1R-directed therapies in the context of allogeneic HSCT.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131116","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}

{"title":"Correction to: Neonatal Neutrophil-mediated Control of Bordetella pertussis Is Disrupted by Pertussis Toxin.","authors":"","doi":"10.1093/jimmun/vkaf255","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf255","url":null,"abstract":"","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112844","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}

{"title":"CD19 and FcγRIIb co-engagement inhibits processes essential to T cell-dependent B-cell responses.","authors":"Daniel M Morelli, Heather C Craig, Xiao Feng, Michele Youd, Mark I Matijevic, Steven M Kerfoot","doi":"10.1093/jimmun/vkaf247","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf247","url":null,"abstract":"<p><p>Obexelimab is an investigational, bifunctional humanized monoclonal antibody that inhibits B-lineage cells by binding CD19 via its Fab region and simultaneously co-engaging the inhibitory receptor FcγRIIb through a modified Fc region. Interactions between B cells and T cells specific for the same Ag are essential for the development of germinal center (GC) B-cell responses and high-affinity antibodies. Mutant mice expressing human FcγRIIb and a mouse obexelimab surrogate (mObx) were used to determine if mObx inhibits these critical interactions between cognate B cells and T cells. In ex vivo experiments, mObx blocked B-cell receptor (BCR)-mediated uptake of Ag-coated beads by splenic follicular (Fo) and marginal zone (MZ) B cells and peritoneal cavity (PerC) B1 cells. Similarly, obexelimab treatment of human B cells significantly reduced BCR-mediated bead uptake ex vivo. mObx-treatment inhibited Ag presentation by splenic B cells to co-cultured T cells, as T-cell proliferation and expression of activation markers CD25 and CD44 were significantly reduced when mObx, but not control anti-CD19 antibody, was added to the co-culture. Finally, prophylactic treatment of mice with mObx effectively blocked the activation of human FcγRIIb-expressing B cells and the development of an Ag-specific GC response in vivo. Treatment after GC onset resulted in dissolution of the GC. Collectively, these data demonstrate that CD19/FcγRIIb co-engagement effectively suppresses processes essential to support T cell-dependent B-cell responses, which is consistent with the proposed mechanism of action of obexelimab.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112873","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}