Clinical & Translational Immunology最新文献

{"title":"Alterations of circulating innate lymphoid cells in recent-onset type 1 diabetes","authors":"Ariadna Roig,&nbsp;David Perna-Barrull,&nbsp;Eva Aguilera,&nbsp;Sebastián Pérez,&nbsp; Marta Vives-Pi,&nbsp;Raquel Planas","doi":"10.1002/cti2.70109","DOIUrl":"https://doi.org/10.1002/cti2.70109","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Type 1 diabetes (T1D) is driven by autoreactive T lymphocytes with contributions from innate immune compartments, yet early innate immune alterations associated with autoimmune amplification remain incompletely defined. We aimed at investigating whether circulating innate lymphoid cells (ILCs) contribute to these processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Circulating ILCs from patients with recent-onset T1D (<i>n</i> = 12) and age-matched healthy donors were analysed by spectral flow cytometry and targeted gene-expression profiling of purified ILC progenitors (ILCP). Metabolic and inflammatory modulation of ILC activation was assessed in vitro. Antigen presentation to autologous memory CD4 T cells was functionally evaluated. Findings were examined across disease progression in NOD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Total ILC frequencies were comparable between groups; however, ILC1 and ILCP from T1D patients displayed increased activation markers (CD69, HLA-DR). ILCP exhibited reduced expression of migratory (CCR7, CCR6) and regulatory-associated genes (ICOS, CD58). Glycolytic inhibition selectively attenuated ILCP activation, supporting a metabolic contribution. IL-1β, and to a lesser extent IFNγ, enhanced antigen presentation-associated phenotypes in human circulating ILCs. Upon inflammatory pre-activation, insulin peptide-loaded circulating ILCs upregulated MHC class II–associated markers and induced antigen-specific activation of autologous CD4⁺ memory T cells. NOD mice recapitulated ILC activation and MHC class II expression patterns during diabetes progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Circulating ILCs in recent-onset T1D display a pre-activated, metabolically regulated phenotype with functional antigen-presenting capacity, supporting a potential role in autoimmune amplification. The findings of this exploratory study provide translational insight into innate immune dysregulation associated with recent-onset T1D.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148173680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity","authors":"Yizhuo Wang,&nbsp;Divya Ramnath,&nbsp;Kaustav Das Gupta,&nbsp;P Prakrithi,&nbsp;Kavita Bisht,&nbsp;Gregory C Miller,&nbsp;Zherui Xiong,&nbsp;Yujun Wan,&nbsp;Ellen N Tejo,&nbsp;James EB Curson,&nbsp;Rishika Abrol,&nbsp;Sahar Keshvari,&nbsp;Kimberley S Gunther,&nbsp;Jordan D Atkinson,&nbsp;Zhixuan Loh,&nbsp;Jessica A Engel,&nbsp;Christian R Engwerda,&nbsp;Sabrina Sofia Burgener,&nbsp;Kate Schroder,&nbsp;David P Fairlie,&nbsp;Andrew D Clouston,&nbsp;Elizabeth E Powell,&nbsp;Katharine M Irvine,&nbsp;Mitchell A Sullivan,&nbsp;Jean-Pierre Lévesque,&nbsp;Quan Nguyen,&nbsp;Matthew J Sweet,&nbsp;Denuja Karunakaran","doi":"10.1002/cti2.70100","DOIUrl":"https://doi.org/10.1002/cti2.70100","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Histone deacetylase 7 (HDAC7), a classical HDAC family member, promotes LPS-inducible glycolysis and inflammatory mediator production in macrophages, innate immune cells that contribute to pathology in metabolic diseases. Here, we investigated myeloid HDAC7 functions in obesity-driven metabolic disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used gain- and loss-of-function genetic approaches in mice to investigate myeloid HDAC7 functions in hepatic inflammation and metabolic disease, as well as associations with hepatic gene signatures characteristic of advanced chronic liver disease (CLD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transgenic expression of <i>Hdac7</i> in myeloid cells increased liver inflammation and liver mRNA levels of <i>Ccl2</i> and <i>Il1b</i>, key inflammatory mediators linked to CLD. Liver glycogen levels were also decreased, another feature of CLD. Transgenic expression of <i>Hdac7</i> in myeloid cells mimicked the hepatic inflammatory phenotype that was observed in mice fed a high fat, high cholesterol and high sucrose (HFHCHS) diet, an obesity model that mimics some features of metabolic dysfunction-associated steatotic liver disease. In myeloid <i>Hdac7</i> transgenic mice fed a HFHCHS diet, relative weight gain was increased, fasted glucose levels were elevated, and glucose tolerance was dysregulated by comparison to control mice. Conversely, fasted blood glucose levels were reduced and glucose tolerance was improved in myeloid <i>Hdac7</i>-deleted mice on a HFHCHS diet. <i>HDAC7</i> mRNA levels were also elevated in the livers of people with advanced CLD and spatial transcriptomics revealed that myeloid HDAC7 directs hepatic gene signatures characteristic of advanced CLD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Myeloid HDAC7 contributes to hepatic inflammation and systemic glucose dysregulation in a mouse model of obesity and liver inflammation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 6","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148099952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148077795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant intra-epithelial lymphocytes cause enterocyte cell death in refractory celiac disease by CD103-β7-receptor-mediated granzyme-B degranulation which can be restored by etrolizumab.","authors":"Daan A R Castelijn, Jolanda M W van de Water, Laura R de Baaij, Bridget S McGlinchy, Michelle van Leeuwen, Sander P J Joosten, Nikita Alberts, Margherita Rossi, Martine Reijm, Jolien C Hollander, Petra Bonnet, Yvonne M C Kooy-Winkelaar, Frits Koning, Steven T Pals, Gerd Bouma, Chris J L M Meijer, Hetty J Bontkes, Chris J J Mulder, Saskia A G M Cillessen","doi":"10.1002/cti2.70099","DOIUrl":"10.1002/cti2.70099","url":null,"abstract":"<p><strong>Objectives: </strong>Refractory celiac disease type II (RCDII) is an intestinal tumor of aberrant intra-epithelial T-lymphocytes (IEL). The severe enteropathy found in RCDII is caused by aberrant IEL that exert cytotoxicity against enterocytes. In this study, we investigated the cell death mechanism responsible for villous atrophy in RCDII.</p><p><strong>Methods: </strong>Aberrant IEL were isolated from duodenal biopsies of RCDII patients. Enterocyte and RCDII patient-derived cell lines and human small intestinal organoids were used. mRNA expression was determined with reverse transcriptase-multiplex ligation-dependent probe amplification. Protein expression, degranulation and enterocyte killing were measured using flow cytometry, immunofluorescence or bright field microscopy. Secretion of granzyme-B was detected by enzyme immunoassay.</p><p><strong>Results: </strong>Levels of granzyme-B expression were significantly upregulated in aberrant IEL of RCDII patients compared to patients with celiac disease (CD) on gluten-free diet (<i>P</i> = 0.0001) and correlated with severity of villous atrophy and clinical response to therapy. Killing of intestinal epithelial cells was caused by granzyme-B. For granzyme-B degranulation and subsequent cytotoxicity, cell-cell binding via the CD103-receptor, which was upregulated on aberrant IEL, was essential. In a preclinical model, aberrant IEL migrated to the intestinal organoids and induced organoid disintegration and CD103-dependent cell death. Targeting CD103-heterodimeric partner β7 with therapeutic monoclonal antibody etrolizumab prevented enterocyte cell killing and resulted in survival of organoids.</p><p><strong>Conclusion: </strong>Killing of enterocytes in RCDII patients depends on degranulation of granzyme-B by aberrant IEL through CD103-β7 binding. By blocking this interaction, etrolizumab restores the intestinal epithelium and therefore should be considered as potential therapy for RCDII patients.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 ","pages":"e70099"},"PeriodicalIF":3.4,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13175919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148077796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148075398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148075397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of tumor-infiltrating gamma-delta T cells in human colorectal cancer with MHC-I loss.","authors":"Tianming A Li, Luke T Quigley, Kok Fei Chan, David S Williams, Lisa A Mielke, Andreas Behren, Jessica Da Gama Duarte","doi":"10.1002/cti2.70097","DOIUrl":"10.1002/cti2.70097","url":null,"abstract":"<p><strong>Objectives: </strong>Gamma-delta (γδ) T cells have been associated with favorable prognoses across several malignancies, underscoring their potential as targets for novel immunotherapies. These unconventional T lymphocytes exhibit an intrinsic tropism for the tumor microenvironment, largely driven by their capacity to recognize stress-induced antigens characteristic of metabolically dysregulated tumors. Unlike the mechanism governing conventional cytotoxic CD8⁺ alpha-beta (αβ) T cells, γδ T-cell receptors can engage tumor cell moieties independent of major histocompatibility complex class-I (MHC-I) and human leukocyte class-I molecules. Therefore, γδ T cells may have a pivotal role in the immune response to beta-2 microglobulin-mutated MHC-I negative (MHC-I^-) colorectal cancers (CRCs) with deficient mismatch repair.</p><p><strong>Methods: </strong>To determine whether γδ T-cell mobilisation extends to diverse aetiologies of MHC-I loss, we used multispectral immunohistochemistry to stain 150 stage I-IV primary CRC tissues, across eight tissue microarrays.</p><p><strong>Results: </strong>Our investigation revealed MHC-I loss in ~30% of CRC primary tumors across all disease stages, with a notable increase in stromal γδ T-cell frequency and activation status among stage III cases. Importantly, these findings extend previous observations largely confined to mismatch repair-deficient CRC by demonstrating that stromal γδ T-cell enrichment associated with MHC-I loss also occurs in mismatch repair-proficient tumors, suggesting a broader role for γδ T cells in immune surveillance of MHC-I-deficient CRC.</p><p><strong>Conclusion: </strong>These data highlight the potential of γδ T cells in counteracting immune evasive MHC-I^- tumors, thereby offering a robust rationale for their strategic deployment in next-generation immunotherapy regimens.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 ","pages":"e70097"},"PeriodicalIF":3.4,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13161889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148066743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"15 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148066744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}