Journal of immunology最新文献_第2页

WDFY1-expressing follicular dendritic cells play a critical role in lupus development in cGVHD mouse model. 在cGVHD小鼠模型中，表达wdfy1的滤泡树突状细胞在狼疮的发展中起关键作用。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-04-01 DOI: 10.1093/jimmun/vkaf017

Yuxuan Zhen, Wen-Hai Shao

{"title":"WDFY1-expressing follicular dendritic cells play a critical role in lupus development in cGVHD mouse model.","authors":"Yuxuan Zhen, Wen-Hai Shao","doi":"10.1093/jimmun/vkaf017","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf017","url":null,"abstract":"Follicular dendritic cells (FDCs) retain Ag-containing immune complexes (ICs), facilitate the selection of high-affinity antibodies, and protect B cells in germinal centers (GCs) from apoptosis. In systemic lupus erythematosus patients, apoptotic debris is found on the surface of FDCs. However, the mechanisms by which FDCs engage the protected autoreactive B cells remain unclear. WD repeat and FYVE domain-containing protein 1 (WDFY1) is an adaptor protein involved in endocytic/vacuolar membrane trafficking. We found that FDCs express a high level of WDFY1, which is required for their IC presentation. C57BL/6 mice deficient in WDFY1 generated significantly lesser titers of anti-dsDNA and anti-chromatin autoantibodies (autoAbs) than WDFY1-sufficient mice receiving an equal amount of CD4+ T cells from bm12 mice in the mouse model of inducible lupus. Decreased autoAb production in WDFY1-deficient mice correlates with less GC formation and fewer T and GC B cells in the follicle. Interestingly, T cells from WDFY1-KO mice remain capable of inducing comparable chronic graft-versus-host disease (cGVHD) in host bm12 mice as the T cells from WT mice. B cells from WDFY1-KO mice also remain capable of being fully activated and differentiated in response to independent Ag challenges. Immunofluorescence staining reveals reduced binding of ICs with FDCs in WDFY1-KO mice compared to WT control mice. Mixed leukocyte reaction results show no intrinsic defect in B cells. B-cell reconstitution in Rag1-KO mice also revealed that WDFY1 is critical for FDCs. Collectively, our studies indicate that WDFY1 knockout impairs the normal functioning of FDCs, resulting in reduced autoAb response to cGVHD.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764024","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

Accurate enumeration of pathogen-specific and virtual memory CD8 T cells after infection. 感染后病原体特异性和虚拟记忆性CD8 T细胞的准确计数。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-04-01 DOI: 10.1093/jimmun/vkaf007

Roger R Berton, Mohammad Heidarian, Shravan Kumar Kannan, Manan Shah, Noah S Butler, John T Harty, Vladimir P Badovinac

{"title":"Accurate enumeration of pathogen-specific and virtual memory CD8 T cells after infection.","authors":"Roger R Berton, Mohammad Heidarian, Shravan Kumar Kannan, Manan Shah, Noah S Butler, John T Harty, Vladimir P Badovinac","doi":"10.1093/jimmun/vkaf007","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf007","url":null,"abstract":"Establishing the magnitude and kinetics of polyclonal Ag-specific CD8 T-cell responses, in addition to their functional fitness, is critical for evaluating a host's ability to respond to different kinds of infections and/or immunizations. To track CD8 T-cell responses during infection, a surrogate-activation-marker approach (CD8αloCD11ahi) is used to distinguish naïve and Ag-experienced effector/memory CD8 T cells in vivo. However, semidifferentiated virtual memory (Tvm) CD8 T cells have recently been identified in uninfected/unmanipulated mice that display a phenotype similar to Ag-experienced cells. Therefore, magnitude and breadth of CD8 T-cell responses may be overestimated when responses are profiled using only CD8α/CD11a markers. Thus, to precisely define and distinguish Tvm from pathogen-specific CD8 T cells during bacterial, parasitic, and viral infections, pathogen-specific sensor TCR-Tg cells were adoptively transferred prior to challenge. We demonstrate that Tvm CD8 T cells are found in CD8αloCD11ahi-defined Ag-experienced CD8 T cells but can be parsed out in infected host with their CD49d-CD44hiCD122hi expression pattern. However, this approach presents potential limitations as CD49d+ Ag-specific CD8 T cells can lose CD49d expression and adopt a Tvm-like phenotype depending on their Ag-stimulation history, age, and naïve CD8 T-cell precursor frequency before the infection. Importantly, Tvm cells contribute to the breadth of the CD8 T-cell response, and their contribution depends on type of infection, time after infection, and tissue examined. Thus, these data define limitations in our ability to resolve between pathogen/Ag-specific and Tvm CD8 T-cell responses during infection, a notion of direct relevance for experimental murine studies designed to follow CD8 T-cell responses in vivo.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753024","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 respiratory CD8+ T-cell immunity by suppressive monocyte-like dendritic cells (MCs). 抑制单核细胞样树突状细胞（MCs）调节呼吸道CD8+ t细胞免疫。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-31 DOI: 10.1093/jimmun/vkae059

Katie L Reagin, Kimberly E Oliva, Matthew R Hansen, Chris D Slade, Wendy T Watford, Kimberly D Klonowski

{"title":"Regulation of respiratory CD8+ T-cell immunity by suppressive monocyte-like dendritic cells (MCs).","authors":"Katie L Reagin, Kimberly E Oliva, Matthew R Hansen, Chris D Slade, Wendy T Watford, Kimberly D Klonowski","doi":"10.1093/jimmun/vkae059","DOIUrl":"https://doi.org/10.1093/jimmun/vkae059","url":null,"abstract":"Active immune suppression can mediate the balance between protective cellular immunity and harmful immunopathology. This suppression can occur locally, at an infection site, or in regional draining lymph nodes (dLNs). Immune regulation is of particular importance in sites such as the lung where aberrant immunopathology can result in loss of tissue function and respiratory failure. We have recently identified a novel population of CD11b+CD103+CCR2+ monocyte-like dendritic cells (MCs) which directly suppress CD8+ T-cell proliferation in vitro. Respiratory infection of mice with RNA viruses recruits these MCs either exclusively to the dLN (after vesicular stomatitis virus infection) or both the dLN and site of viral replication (after influenza infection). Here we show that depletion of MCs from the dLN of mice using CCR2-DTR bone marrow chimeras results in enhanced respiratory CD8+ T-cell responses and lung tissue-resident memory cell (TRM) formation which correlated with enhanced antiviral responses upon heterologous VSV challenge. Conversely, depletion of MCs from both the dLN and respiratory tract following influenza infection results in enhanced respiratory CD8+ T-cell responses coupled with fatal immunopathology. Together, these data suggest that suppressive MCs govern key aspects of respiratory CD8+ T-cell immunity, thereby balancing immunity and adverse pathology in the context of viral infection.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753030","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

Enhancing activity of FcαRI-bispecific antibodies using glycoengineering. 糖工程增强fc α ri双特异性抗体活性。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-28 DOI: 10.1093/jimmun/vkaf027

Céline A N Sewnath, Timon Damelang, Arthur E H Bentlage, Luuk Ten Kroode, Cornelis W Tuk, Remco Visser, Manfred Wuhrer, Julie Van Coillie, Theo Rispens, Marjolein van Egmond, Gestur Vidarsson

{"title":"Enhancing activity of FcαRI-bispecific antibodies using glycoengineering.","authors":"Céline A N Sewnath, Timon Damelang, Arthur E H Bentlage, Luuk Ten Kroode, Cornelis W Tuk, Remco Visser, Manfred Wuhrer, Julie Van Coillie, Theo Rispens, Marjolein van Egmond, Gestur Vidarsson","doi":"10.1093/jimmun/vkaf027","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf027","url":null,"abstract":"Macrophages and natural killer (NK) cells can effectively kill tumor cells in the presence of anti-cancer IgG monoclonal antibodies (mAbs), but neutrophils are less effective. We previously showed that IgG1 bispecific antibodies (BsAb), which target the IgA Fc receptor (FcαRI, CD89) and a tumor associated antigen induce effective neutrophil recruitment and tumor cell killing in vivo. Here we investigated if the efficacy of an anti-EGFR (CetuximAb)/FcαRI-bispecific antibody could be further improved by implementing glycoengineering of the IgG-Fc, aimed at increasing FcγRIIIa/b binding and/or complement activity. Fc afucosylation was introduced to enhance antibody-dependent cellular cytotoxicity (ADCC) by FcγRIIIa on NK/macrophages, which can also reduce neutrophil-mediated ADCC through their GPI-linked FcγRIIIb. Fc galactylation was found to enhance antibody hexamerization and thereby complement dependent cytotoxicity (CDC). Low fucosylated BsAbs moderately increased NK cell-mediated tumor cell killing, but did not affect neutrophil-mediated tumor cell killing nor phagocytosis by macrophages. Glycoengineering of these EGFR-specific BsAb, which normally are devoid of CDC-activity, did not enable their complement activities. In conclusion, glycoengineered FcαRI BsAbs increased ADCC by NK cells but had little effect on neutrophil or macrophage mediated tumor killing.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742593","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

Cryptococcosis, tuberculosis, and a kidney cancer fail to fit the atherosclerosis paradigm for foam cell lipid content. 隐球菌病、肺结核和肾癌的泡沫细胞脂质含量不符合动脉粥样硬化范式。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-28 DOI: 10.1093/jimmun/vkaf038

Valentina Guerrini, Brendan Prideaux, Rehan Khan, Selvakumar Subbian, Yina Wang, Evita Sadimin, Siddhi Pawar, Rahul Ukey, Eric A Singer, Chaoyang Xue, Maria Laura Gennaro

{"title":"Cryptococcosis, tuberculosis, and a kidney cancer fail to fit the atherosclerosis paradigm for foam cell lipid content.","authors":"Valentina Guerrini, Brendan Prideaux, Rehan Khan, Selvakumar Subbian, Yina Wang, Evita Sadimin, Siddhi Pawar, Rahul Ukey, Eric A Singer, Chaoyang Xue, Maria Laura Gennaro","doi":"10.1093/jimmun/vkaf038","DOIUrl":"10.1093/jimmun/vkaf038","url":null,"abstract":"Foam cells are dysfunctional, lipid-laden macrophages associated with chronic inflammation of diverse origin. The long-standing paradigm that foam cells are cholesterol-laden derives from atherosclerosis research. We previously showed that, in tuberculosis, foam cells surprisingly accumulate triglycerides. Here, we utilized bacterial (Mycobacterium tuberculosis), fungal (Cryptococcus neoformans), and human papillary renal cell carcinoma (pRCC) models to address the need for a new explanation of foam cell biogenesis. We applied mass spectrometry-based imaging to assess the spatial distribution of storage lipids relative to foam-cell-rich areas in lesional tissues, and we characterized lipid-laden macrophages generated under corresponding in vitro conditions. The in vivo data and the in vitro findings showed that cryptococcus-infected macrophages accumulate triglycerides, while macrophages exposed to pRCC-conditioned-medium accumulated both triglycerides and cholesterol. Moreover, Cryptococcus- and Mycobacterium-infected macrophages accumulated triglycerides in different ways. Collectively, the data show that the molecular events underlying foam cell formation are specific to disease and microenvironment. Since foam cells are potential therapeutic targets, recognizing that their formation is disease-specific opens new biomedical research directions.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742397","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

Transcriptional and chromatin accessibility landscapes of hematopoiesis in a mouse model of breast cancer. 乳腺癌小鼠模型中造血的转录和染色质可及性景观。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-27 DOI: 10.1093/jimmun/vkaf026

Changxu Fan, Jun Wu, Derek A G Barisas, Xiaoyun Xing, Yoojung Kwon, Kyunghee Choi, Ting Wang

{"title":"Transcriptional and chromatin accessibility landscapes of hematopoiesis in a mouse model of breast cancer.","authors":"Changxu Fan, Jun Wu, Derek A G Barisas, Xiaoyun Xing, Yoojung Kwon, Kyunghee Choi, Ting Wang","doi":"10.1093/jimmun/vkaf026","DOIUrl":"10.1093/jimmun/vkaf026","url":null,"abstract":"Increased myeloid lineage production, termed myeloid skewing, leading to decreased tumor immunity, is a hallmark of aberrant hematopoiesis associated with cancer. It is believed that myeloid skewing may occur at the hematopoietic stem and progenitor cells (HSPCs) level to elicit hematopoietic changes. However, our understanding of the underlying molecular mechanisms remains incomplete. Here, we characterize the transcriptional and chromatin accessibility landscapes of bone marrow and splenic hematopoietic progenitors in the MMTV-PyMT mouse model of breast cancer using single-cell ATAC + RNA sequencing. We show that HSPCs in the bone marrow (BM) of the tumor-bearing mice show a modest upregulation of the myeloid-bias transcriptional signature without significant chromatin accessibility changes. By contrast, dendritic cell (DC) progenitors exhibit the most prominent transcriptional and chromatin changes, showing a signature of STAT3, CEBP, and non-DC myeloid gene activation. Compared to BM, splenic HSPCs exhibit a Notch signaling signature associated with erythroid commitment rather than further upregulation of the myeloid-bias signature. In addition, we also identify a cluster of splenic HSPCs in tumor-bearing animals with a transcriptional signature of mobilization. Our paired chromatin data suggest that AP-1 factors play a crucial role in driving this HSPC mobilization signature. Overall, we provide a comprehensive dataset for understanding the hematopoietic consequences of cancer.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730431","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

ERAP1-dependent extreme antigen processing efficacy can govern MHC class I expression hierarchy. erap1依赖的极端抗原加工效率可以控制MHC I类表达层次。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-27 DOI: 10.1093/jimmun/vkaf013

Jacqueline Leib, Emmanuelle Waeckel-Énée, Sylvie Fabrega, Nadia Keelan, Alice Senni, François-Xavier Mauvais, Rebecca Deprez-Poulain, Barbara Bertocci, Peter van Endert

{"title":"ERAP1-dependent extreme antigen processing efficacy can govern MHC class I expression hierarchy.","authors":"Jacqueline Leib, Emmanuelle Waeckel-Énée, Sylvie Fabrega, Nadia Keelan, Alice Senni, François-Xavier Mauvais, Rebecca Deprez-Poulain, Barbara Bertocci, Peter van Endert","doi":"10.1093/jimmun/vkaf013","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf013","url":null,"abstract":"Peptide presentation by major histocompatibility complex (MHC) class I molecules enables CD8+ T lymphocytes to monitor the intracellular proteome of tissue cells. CD8+ T cell priming and acquisition of effector functions is affected by cognate peptide-MHC-I complex density on the cell surface, which partly depends on the efficacy of intracellular proteolytic peptide generation. Peptide generation frequently requires final trimming by the human aminopeptidases ERAP1, ERAP2, and IRAP. All display genetic polymorphism associated with the risk of multiple autoimmune diseases but also some cancers. This finding has prompted interest in the development of small molecule inhibitors to enhance antitumor or conversely attenuate autoreactive T cell responses. However, efficient assays for assessment of inhibitor effects are wanting. We describe the development of an assay for quantitative assessment by flow cytometry of selective inhibitor effects on peptide trimming both in the endogenous MHC-I processing pathway and in cross-presentation. We use the assay to identify a selective ERAP2 inhibitor and show that inhibitor effects can be read out not only through assessing a specific peptide-MHC complexes but also by measuring cell surface levels of bulk MHC-I molecules. Next to its practical interest as tool for inhibitor testing, our assay highlights how ERAP1-dependent immunodominance of a single epitope processed with exceptional efficacy can have a massive effect on the immunopeptidomic identity of cells presented to CD8+ T cells. We propose that ERAP effects on the presentation of such rare and exceptionally immunodominant epitopes may underlie the epistatic genetic associations of ERAP polymorphism with HLA class I-linked autoimmune diseases.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730409","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

Hippo-YAP pathway regulates antimicrobial immune response in obscure puffer Takifugu obscurus. Hippo-YAP通路调控暗鲀抗微生物免疫反应。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-26 DOI: 10.1093/jimmun/vkaf011

Ruixia Wang, Ying Huang, Yan Shi, Zhe Zhao

{"title":"Hippo-YAP pathway regulates antimicrobial immune response in obscure puffer Takifugu obscurus.","authors":"Ruixia Wang, Ying Huang, Yan Shi, Zhe Zhao","doi":"10.1093/jimmun/vkaf011","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf011","url":null,"abstract":"The Hippo signaling pathway plays an important role in regulating host immune responses. However, few studies have explored its role in fish. Therefore, this study aimed to investigate the mechanism by which the Hippo pathway regulates the expression of antimicrobial peptides (AMPs) in obscure puffer Takifugu obscurus. After infection with Staphylococcus aureus or Vibrio harveyi, the expression of mammalian STE20-like protein kinase (ToMst) and Yes-associated protein (ToYap) was significantly upregulated in the liver, heart, and kidney of T. obscurus. Additionally, the phosphorylation level of ToMst increased. When ToMst phosphorylation was inhibited, the expression of inhibitor of kappa B (ToIκB) was upregulated, the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (ToNF-κB) from the cytoplasm to the nucleus was inhibited, and the expression of AMPs (ToLyz, ToFerritin, and ToPerforin-1) was downregulated. Conversely, when ToMst was overexpressed, the expression of ToLyz, ToFerritin, and ToPerforin-1 increased. After bacterial stimulation, ToYap was translocated from the nucleus to the cytoplasm. When the expression of ToYap was knocked down by RNA interference, the expression of ToIκB in the kidney was downregulated, and the expression of ToLyz, ToFerritin, and ToPerforin-1 was upregulated. However, ToYap overexpression inhibited the expression of the three AMP genes. These findings indicate that ToYap negatively regulates the expression of AMPs by regulating the transcriptional activity of ToIκB. These findings reveal the molecular mechanism of the Hippo pathway in the antimicrobial immunity of T. obscurus and contribute to the development of new methods and strategies for treating diseases.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730412","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

Peptide selectivity of killer cell immunoglobulin-like receptors differs with allotypic variation in HLA class I. 杀伤细胞免疫球蛋白样受体的肽选择性随HLA I类异型变异而异。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-24 DOI: 10.1093/jimmun/vkaf003

Philippa M Saunders, Patricia T Illing, Lachlan Coin, Shu Cheng Wong, Clare V L Oates, Anthony W Purcell, Andrew G Brooks

{"title":"Peptide selectivity of killer cell immunoglobulin-like receptors differs with allotypic variation in HLA class I.","authors":"Philippa M Saunders, Patricia T Illing, Lachlan Coin, Shu Cheng Wong, Clare V L Oates, Anthony W Purcell, Andrew G Brooks","doi":"10.1093/jimmun/vkaf003","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf003","url":null,"abstract":"Natural killer (NK) cell activation is regulated by killer cell immunoglobulin-like receptors (KIRs) that recognize human leukocyte antigen (HLA) class I molecules. While polymorphism in HLA can directly impact these interactions, the extent to which the HLA-associated peptide repertoire modulates NK cell function is less well understood. Therefore, the peptide requirements for the recognition of 2 ligands, HLA-B*57:01 and HLA-A*24:02, that share similar KIR3DL1 binding residues but differ in their capacity to inhibit human NK cells were assessed. Immunopeptidome and functional analyses of endogenous peptides associated with each allotype showed that both repertoires contained peptides capable of facilitating or impairing KIR3DL1-dependent recognition of target cells. While distinct sequence features at positions 7 and 8 of the bound peptide similarly impacted recognition of both HLA class I allotypes, HLA-B*57:01 remained a more potent ligand overall. In silico analyses suggested that most peptides presented by HLA-B*57:01 would facilitate KIR3DL1 engagement, whereas the peptide repertoire of HLA-A*24:02 possessed fewer peptides predicted to support strong KIR3DL1 recognition. Nevertheless, the exogenous addition of highly permissive peptides to cells expressing HLA-A*24:02 could bolster KIR3DL1-mediated NK cell inhibition of peptide-competent cells to levels seen with HLA-B*57:01. Together, these data indicate that allotypic differences in peptide repertoire impact KIR recognition of HLA class I and suggest that NK cells have the potential to sense infection- or transformation-induced repertoire perturbations, particularly when the intrinsic KIR/HLA interactions are of modest avidity.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700043","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

Combination therapy blocking TNF superfamily members 14 and 15 reverses pulmonary fibrosis. 阻断TNF超家族成员14和15的联合治疗可逆转肺纤维化。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-03-24 DOI: 10.1093/jimmun/vkaf002

Hope Steele, Ashley Willicut, Garrison Dell, Andrew Ghastine, Xinh-Xinh Nguyen, Paul Lembicz, Hailey Doerflein, Therese Suchoski, Elizabeth Kato, Carol Feghali-Bostwick, Michael Croft, Rana Herro

{"title":"Combination therapy blocking TNF superfamily members 14 and 15 reverses pulmonary fibrosis.","authors":"Hope Steele, Ashley Willicut, Garrison Dell, Andrew Ghastine, Xinh-Xinh Nguyen, Paul Lembicz, Hailey Doerflein, Therese Suchoski, Elizabeth Kato, Carol Feghali-Bostwick, Michael Croft, Rana Herro","doi":"10.1093/jimmun/vkaf002","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf002","url":null,"abstract":"Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis and tissue remodeling in the clinic. Thus, there is an unmet need to develop novel antifibrotic drugs capable of reversing disease. Our lab has identified two novel mediators of pulmonary fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Aside from their inflammatory roles, LIGHT and TL1A can directly activate structural cells involved in fibrosis, which express their receptors. Here, we show that LIGHT and TL1A receptors are both significantly elevated in patient pulmonary fibrosis biopsies as compared with healthy control lungs. Using gain-of-function studies, we found that LIGHT and TL1A can drive airway remodeling independently of one another. Furthermore, these TNFSF members synergize to maximize airway inflammation and fibrosis. We show that the combinatorial blockade of LIGHT and TL1A limits transforming growth factor β-driven profibrotic effects on fibroblasts in vitro. Moreover, LIGHT and TL1A stimulation of human epithelial cells and fibroblasts reveal distinct fibrotic signatures, including additive and synergistic profibrotic activities, in addition to some redundant profibrotic functions. Importantly, using antagonistic reagents neutralizing both LIGHT and TL1A signaling concomitantly post-disease onset in a bleomycin mouse model of pulmonary fibrosis, we observe a significant decrease in collagen deposition and smooth muscle accumulation as opposed to respective monotherapies blocking each molecule in isolation. This work highlights a therapeutic need to concomitantly target LIGHT and TL1A for treatment of pulmonary fibrosis disorders in humans.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699561","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