Journal of immunology最新文献

{"title":"CD27 costimulation supports metabolic fitness of CD4+ T cells by enhancing de novo nucleotide and protein synthesis.","authors":"Thi Tran Ngoc Minh, Lotte J Verleng, Ellen Schrama, Julia Busselaar, Mo D Staal, Evert de Vries, Jacqueline D H Anholts, Celia R Berkers, Jannie Borst, Esther A Zaal, Sander de Kivit","doi":"10.1093/jimmun/vkaf075","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf075","url":null,"abstract":"<p><p>T cells undergo many metabolic changes throughout the different phases of their response in lymphoid and nonlymphoid tissues. Cell metabolism meets demands for energy and biosynthesis, particularly during cell division and effector differentiation. As costimulatory receptors, CD28 and various TNF receptor (TNFR) family members shape T-cell clonal expansion, survival and effector functions and are important clinical targets. While CD28 is acknowledged as a metabolic regulator, little is known about how TNFRs shape T-cell metabolism. We here identify TNFR family member CD27 as a metabolic regulator in activated human CD4+ T cells. In the context of CD3 signaling and CD28 costimulation, CD27 proved to regulate specific metabolic functions, as determined by metabolomics and metabolic tracer experiments. CD27 costimulation supported upregulation of glycolysis, the pentose phosphate pathway and the TCA cycle, increasing the use of glucose-derived carbon and glutamine-derived nitrogen as building blocks for de novo nucleotide synthesis. It also promoted uptake of amino acids (AAs) and modulated pathways of AA metabolism. Accordingly, CD27 costimulation boosted protein translation in CD3- and CD3/CD28-activated CD4+ T cells, which proceeded via enhanced mTOR pathway activation. Remarkably, CD27, OX40 and 4-1BB all enhanced CD3-induced mTOR signaling, but only CD27 could overrule inhibitory PD-1 signaling. CD27 costimulation increased IL-2, IFNγ and TNFα production by CD3-activated CD4+ T cells, also in presence of PD-1 signaling. Next to previously defined beneficial effects of CD27 on activated T-cell survival and CTL differentiation and Th1 effector differentiation, these data support its essential contribution to T-cell metabolism and its relevance as a therapeutic target.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144016713","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":"Site-specific labeling uncovers differences in levels and distribution of B-cell receptors of different isotypes on primary B cells.","authors":"Djenet Bousbaine, Eugene M Obeng, Zeyang Li, Tao Fang, Ross W Cheloha, Hidde L Ploegh, Nicholas McCaul","doi":"10.1093/jimmun/vkaf062","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf062","url":null,"abstract":"<p><p>Expression of the BCR is essential for survival, development, and effector functions of B cells. Naive B cells express surface IgM and IgD, while surface IgG1 is expressed by class-switched (memory) B cells. Despite similar overall structures, the different BCR isotypes show differences in distribution and expression levels. The dynamics of BCR behavior have been difficult to explore owing to a lack of appropriate tools that can track the BCR without causing concomitant activation. Using CRISPR-Cas9, we inserted a sortase recognition motif (LPETG [LeuProGluThrGly]) at the C-terminus of the OB1 transnuclear ovalbumin-specific Cκ chain (Igκ-LPETG mice). The surface BCR from Igκ-LPETG mice is fully functional and can be labeled site-specifically with biotin or fluorophores. Igκ-LPETG mice show near-normal B-cell development, with an increase in Igλ-producing cells, presumably due to massive contraction of the κ locus V-region cluster upon V-J recombination to generate the OB1 light chain. Using the Igκ-LPETG mice, we compared organization and density of BCRs on the surface of IgM/IgD+ B cells bearing a wild-type (WT) heavy chain locus and IgG1 B cells in the OB1 model. The density of IgG1 BCRs is much reduced compared to IgM/IgD BCRs on primary B cells. Upon activation, IgM/IgD BCRs are found in detergent-insoluble domains, whereas IgG1 BCRs are not. The isotype of the Ig heavy chain thus contributes to surface expression and nanoscale organization of the BCR.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015394","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":"Immunological biomarkers of aging.","authors":"Fei Wu, Wei-Chieh Mu, Nikola T Markov, Matias Fuentealba, Heather Halaweh, Fiona Senchyna, Max N Manwaring-Mueller, Daniel A Winer, David Furman","doi":"10.1093/jimmun/vkae036","DOIUrl":"10.1093/jimmun/vkae036","url":null,"abstract":"<p><p>The immune system has long been recognized for its critical role in the elimination of pathogens and the development of autoimmune diseases, but recent evidence demonstrates that it also contributes to noncommunicable diseases associated with biological aging processes, such as cancer, cardiovascular disease, neurodegeneration, and frailty. This review examines immunological biomarkers of aging, focusing on how the immune system evolves with age and its impact on health and disease. It discusses the historical development of immunological assessments, technological advancements, and the creation of novel biomarkers and models to study immune aging. We also explore the clinical implications of immune aging, such as increased susceptibility to infectious diseases, poor vaccine responses, and a higher incidence of noncommunicable diseases. In summary, we provide a comprehensive overview of current research, highlight the clinical relevance of immune aging, and identify gaps in knowledge that require further investigation.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"214 5","pages":"889-902"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181413","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}

{"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":"10.1093/jimmun/vkae050","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1008-1021"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123218/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bcl-xL is important for the antiapoptotic activity of Gfi1 and is upregulated by Gfi1 through hemgn.","authors":"Binod G C, Pei Du, Yangyang Zhang, Li Yang, Fan Dong","doi":"10.1093/jimmun/vkae066","DOIUrl":"10.1093/jimmun/vkae066","url":null,"abstract":"<p><p>Gfi1 is a transcriptional repressor that plays a critical role in hematopoiesis. Gfi1 represses its target genes primarily through interacting with the histone demethylase LSD1 via its SNAG domain. A major function of Gfi1 is to inhibit DNA damage-induced apoptosis through its involvement in post-translational modifications and subsequent inhibition of p53 protein, and in PRMT1-dependent methylation of MRE11 and 53BP1, which is necessary for these proteins to function in DNA repair. We show here that Gfi1 inhibited apoptosis induced not only by DNA damage but also by growth factor withdrawal, inhibitory cytokine TGF-β and MYC activation. We further demonstrate that Gfi1 upregulated the expression of the pro-survival Bcl-2 family member Bcl-xL in a manner that was independent of p53. Bcl-xL overexpression partially rescued the hypersensitivity to DNA damage of Gfi1-knocked down leukemic cells and Gfi1-deficient mouse primary bone marrow (BM) cells. In contrast, Bcl-xL knockdown partially abolished the protective effect of Gfi1 on DNA damage-induced apoptosis. Notably, interaction with LSD1 was required and sufficient for Gfi1-mediaed upregulation of Bcl-xL, suggesting that Gfi1 may augment Bcl-xL expression by an indirect mechanism. We further demonstrate that Bcl-xL upregulation by Gfi1 was dependent on Hemgn upregulation, which results from Gfi1-mediated repression of PU.1. Our data reveal a novel mechanism by which Gfi1 inhibits apoptosis.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"1046-1058"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015379","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}

{"title":"Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.","authors":"KayLee K Steiner, Arissa C Young, Andrew R Patterson, Ayaka Sugiura, McLane J Watson, Samuel E J Preston, Anton Zhelonkin, Erin Q Jennings, Channing Chi, Darren R Heintzman, Andrew P Pahnke, Yasmine T Toudji, Zaid Hatem, Matthew Z Madden, Emily N Arner, Allison E Sewell, Allison K Blount, Richmond Okparaugo, Emilia Fallman, Evan S Krystofiak, Ryan D Sheldon, Katherine N Gibson-Corley, Kelsey Voss, Sara M Nowinski, Russell G Jones, Denis A Mogilenko, Jeffrey C Rathmell","doi":"10.1093/jimmun/vkaf034","DOIUrl":"10.1093/jimmun/vkaf034","url":null,"abstract":"<p><p>Imbalanced effector and regulatory CD4+ T cell subsets drive many inflammatory diseases. These T cell subsets rely on distinct metabolic programs, modulation of which differentially affects T cell fate and function. Lipid metabolism is fundamental yet remains poorly understood across CD4+ T cell subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid metabolism genes and pathways essential for T cell functions. These screens established mitochondrial fatty acid synthesis genes Mecr, Mcat, and Oxsm as key metabolic regulators. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Mecrfl/fl; Cd4cre mice had normal naïve CD4+ and CD8+ T cell numbers, demonstrating that MECR is not essential in homeostatic conditions. However, effector and memory T cells were reduced in Mecr knockout and MECR-deficient CD4+ T cells and proliferated, differentiated, and survived less well than control T cells. Interestingly, T cells ultimately showed signs of mitochondrial stress and dysfunction in the absence of MECR. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced tricarboxylic acid intermediates, and accumulated intracellular iron, which appeared to contribute to increased cell death and sensitivity to ferroptosis. Importantly, MECR-deficient T cells exhibited fitness disadvantages and were less effective at driving disease in an in vivo model of inflammatory bowel disease. Thus, MECR-mediated metabolism broadly supports CD4+ T cell proliferation and survival in vivo. These findings may also provide insight to the immunological state of MECR- and other mitochondrial fatty acid synthesis-deficient patients.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"958-976"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143996132","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}

{"title":"Editor's Note.","authors":"Gail A Bishop","doi":"10.1093/jimmun/vkaf052","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf052","url":null,"abstract":"","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"214 5","pages":"1071"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181885","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":"BCG induced innate immune response heterogeneity and susceptibility to pediatric tuberculosis.","authors":"Christine Anterasian, Anele Gela, Temwa-Dango Mwambene, Javeed A Shah, Josh Ivie, Kimberly A Dill-McFarland, Willem A Hanekom, Michael C Kiritsy, Christopher M Sassetti, Munyaradzi Musvosvi, Mark Hatherill, Thomas J Scriba, Thomas R Hawn","doi":"10.1093/jimmun/vkae062","DOIUrl":"10.1093/jimmun/vkae062","url":null,"abstract":"<p><p>Although immune responses to bacillus Calmette-Guerin (BCG)-vaccination and susceptibility to pediatric tuberculosis (TB) vary across individuals, the underlying cellular mechanism regulating this heterogeneity is poorly understood. We used a nested case-control study with a 2-yr prospective observation period to examine whether genetic variation is associated with BCG-induced innate immune responses and susceptibility to pediatric TB (N = 134 cases, 516 controls) in BCG-vaccinated infants. Whole blood collected at 10 wk of age from 189 control infants was stimulated with BCG or media and examined with flow cytometry to measure BCG-induced PDL1, CD40, and cytokine expression in myeloid (mDC) and plasmacytoid (pDC) dendritic cells, monocytes, and neutrophils. We used a cellular and clinical GWAS to assess for associations between genetic variants, BCG-induced innate immune responses, and susceptibility to TB. We identified 11 lead genetic variants at genome-wide level significance associated with BCG-induced cytokine and surface expression markers including PDL1 (5 pDCs, 3 mDCs, 1 monocytes), CD40 (1 mDCs), and IL-6 (1 monocytes). An IGLL1 variant (rs2096522) was associated with mDC CD40 expression (P = 1.6e-08) and was also discovered as a significant variant using a gene-based method. In the clinical GWAS, we identified 39 lead variants mapping to 74 genes suggestive of an association with susceptibility to pediatric TB (P < 1e-05), but no variant reached genome-wide significance. One clinical lead variant in the PDE8A region (rs1023844, P = 9.6e-07) was also an eQTL and associated with BCG-induced monocyte PDL1 expression. In summary, we identified genetic variants associated with heterogeneity in infant BCG-induced innate immune responses with potential immunoregulatory mechanisms.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"936-946"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12124979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772402","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}

{"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":"10.1093/jimmun/vkaf004","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"947-957"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123212/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cellular factors that impair the germinal center in advanced age.","authors":"William S Foster, Edith Marcial-Juárez, Michelle A Linterman","doi":"10.1093/jimmun/vkae039","DOIUrl":"10.1093/jimmun/vkae039","url":null,"abstract":"<p><p>Long-lasting immunological memory is a core feature of the adaptive immune system that allows an organism to have a potent recall response to foreign agents that have been previously encountered. Persistent humoral immunity is afforded by long-lived memory B cells and plasma cells, which can mature in germinal centers (GCs) in secondary lymphoid organs. The development of new GC-derived immunity diminishes with age, thereby impairing our immune system's response to both natural infections and vaccinations. This review will describe the current knowledge of how aging affects the cells and microenvironment of the GC. A greater understanding of how the GC changes with age, and how to circumvent these changes, will be critical for tailoring vaccines for older people. This area of research is critical given the twenty-first century will witness a doubling of the aging population and an increased frequency of pandemics.</p>","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"862-871"},"PeriodicalIF":3.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615736","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}