Clinical & Translational Immunology最新文献

{"title":"High KRT17 expression in tumour budding indicates immunologically ‘hot’ tumour budding and predicts good survival in patients with colorectal cancer","authors":"Wenfeng Liang,&nbsp;Haiqing Jie,&nbsp;Hao Xie,&nbsp;Yebohao Zhou,&nbsp;Wenxin Li,&nbsp;Liang Huang,&nbsp;Zhenxing Liang,&nbsp;Huashan Liu,&nbsp;Xiaobin Zheng,&nbsp;Ziwei Zeng,&nbsp;Liang Kang","doi":"10.1002/cti2.1495","DOIUrl":"https://doi.org/10.1002/cti2.1495","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically ‘hot’ TB remain poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We quantified the number of TB by haematoxylin–eosin (H&amp;E) sections and the densities of CD3⁺ and CD8⁺ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In a CRC cohort of 351 cases, low-grade TB was associated with high CD3⁺ and CD8⁺ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3⁺ and CD8⁺ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>KRT17 can be employed as a new indicator for distinguishing different immunological TBs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139993990","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":"Phenotypic spectrum in a family with a novel RAC2 p.I21S dominant-activating mutation","authors":"Louisa Ashby,&nbsp;Lydia Chan,&nbsp;Christine Winterbourn,&nbsp;See-Tarn Woon,&nbsp;Paula Keating,&nbsp;Raoul Heller,&nbsp;Rohan Ameratunga,&nbsp;Ignatius Chua,&nbsp;Kuang-Chih Hsiao","doi":"10.1002/cti2.1493","DOIUrl":"10.1002/cti2.1493","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Dominant-activating (DA) lesions in <i>RAC2</i> have been reported in 18 individuals to date. Some have required haematopoietic stem cell transplantation (HSCT) for their (severe) combined immunodeficiency syndrome phenotype. We aimed to investigate clinical and cellular features of a kindred harbouring a novel variant in <i>RAC2</i> p.Ile21Ser (I21S) to better understand DA lesions' phenotypic spectrum.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical and immunological information was collated for seven living individuals from the same kindred with <i>RAC2</i> p.I21S. We evaluated neutrophil morphology, RAC2 protein expression and superoxide production using freshly isolated neutrophils stimulated with phorbol-12-myristate-13-acetate (PMA) and N-formyl-MetLeuPhe (fMLP).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patient 1 (P1, aged 11, male) has a history of bacterial suppurative otitis media, viral and bacterial cutaneous infections. P1's siblings (P2, P3), mother (P4), maternal aunt (P5) and uncle (P6) have similar infection histories. P1's maternal cousin (P7) presented with Burkitt's lymphoma at age 9. All affected individuals are alive and none has required HSCT to date. They have chronic lymphopenia affecting the CD4⁺T and B-cell compartments. P1–3 have isolated reduction in IgM levels whereas the adults universally have normal immunoglobulins. Specific antibody responses are preserved. Affected individuals have neutrophil vacuolation, and their neutrophils have enhanced superoxide production compared to healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p><i>RAC2</i> p.I21S is an activating variant causing notable morphological and functional abnormalities similar to other reported DA mutations. This novel variant expands the broad clinical phenotypic spectrum of <i>RAC2</i> DA lesions, emphasising the need to tailor clinical management according to patients' disease phenotype and severity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1493","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139969324","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":"Whole blood transcriptomics reveals granulocyte colony-stimulating factor as a mediator of cardiopulmonary bypass-induced systemic inflammatory response syndrome","authors":"Katherine R Martin,&nbsp;Cristina Gamell,&nbsp;Tsin Yee Tai,&nbsp;Roberto Bonelli,&nbsp;Jacinta Hansen,&nbsp;James Tatoulis,&nbsp;Monther Alhamdoosh,&nbsp;Nicholas Wilson,&nbsp;Ian Wicks","doi":"10.1002/cti2.1490","DOIUrl":"https://doi.org/10.1002/cti2.1490","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Systemic inflammatory response syndrome (SIRS) is a frequent complication of cardiopulmonary bypass (CPB). SIRS is associated with significant morbidity and mortality, but its pathogenesis remains incompletely understood, and as a result, biomarkers are lacking and treatment remains expectant and supportive. This study aimed to understand the pathophysiological mechanisms driving SIRS induced by CPB and identify novel therapeutic targets that might reduce systemic inflammation and improve patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-one patients undergoing cardiac surgery and CPB were recruited, and blood was sampled before, during and after surgery. SIRS was defined using the American College of Chest Physicians/Society of Critical Care Medicine criteria. We performed immune cell profiling and whole blood transcriptomics and measured individual mediators in plasma/serum to characterise SIRS induced by CPB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Nineteen patients fulfilled criteria for SIRS, with a mean duration of 2.7 days. Neutrophil numbers rose rapidly with CPB and remained elevated for at least 48 h afterwards. Transcriptional signatures associated with neutrophil activation and degranulation were enriched during CPB. We identified a network of cytokines governing these transcriptional changes, including granulocyte colony-stimulating factor (G-CSF), a regulator of neutrophil production and function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We identified neutrophils and G-CSF as major regulators of CPB-induced systemic inflammation. Short-term targeting of G-CSF could provide a novel therapeutic strategy to limit neutrophil-mediated inflammation and tissue damage in SIRS induced by CPB.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1490","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139901690","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":"Effective γδ T-cell clinical therapies: current limitations and future perspectives for cancer immunotherapy","authors":"Isabella A Revesz,&nbsp;Paul Joyce,&nbsp;Lisa M Ebert,&nbsp;Clive A Prestidge","doi":"10.1002/cti2.1492","DOIUrl":"https://doi.org/10.1002/cti2.1492","url":null,"abstract":"<p>γδ T cells are a unique subset of T lymphocytes, exhibiting features of both innate and adaptive immune cells and are involved with cancer immunosurveillance. They present an attractive alternative to conventional T cell-based immunotherapy due, in large part, to their lack of major histocompatibility (MHC) restriction and ability to secrete high levels of cytokines with well-known anti-tumour functions. To date, clinical trials using γδ T cell-based immunotherapy for a range of haematological and solid cancers have yielded limited success compared with <i>in vitro</i> studies. This inability to translate the efficacy of γδ T-cell therapies from preclinical to clinical trials is attributed to a combination of several factors, e.g. γδ T-cell agonists that are commonly used to stimulate populations of these cells have limited cellular uptake yet rely on intracellular mechanisms; administered γδ T cells display low levels of tumour-infiltration; and there is a gap in the understanding of γδ T-cell inhibitory receptors. This review explores the discrepancy between γδ T-cell clinical and preclinical performance and offers viable avenues to overcome these obstacles. Using more direct γδ T-cell agonists, encapsulating these agonists into lipid nanocarriers to improve their pharmacokinetic and pharmacodynamic profiles and the use of combination therapies to overcome checkpoint inhibition and T-cell exhaustion are ways to bridge the gap between preclinical and clinical success. Given the ability to overcome these limitations, the development of a more targeted γδ T-cell agonist-checkpoint blockade combination therapy has the potential for success in clinical trials which has to date remained elusive.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1492","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139901691","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":"Fighting flu: novel CD8+ T-cell targets are required for future influenza vaccines","authors":"Samuel Liwei Leong,&nbsp;Stephanie Gras,&nbsp;Emma J Grant","doi":"10.1002/cti2.1491","DOIUrl":"https://doi.org/10.1002/cti2.1491","url":null,"abstract":"<p>Seasonal influenza viruses continue to cause severe medical and financial complications annually. Although there are many licenced influenza vaccines, there are billions of cases of influenza infection every year, resulting in the death of over half a million individuals. Furthermore, these figures can rise in the event of a pandemic, as seen throughout history, like the 1918 Spanish influenza pandemic (50 million deaths) and the 1968 Hong Kong influenza pandemic (~4 million deaths). In this review, we have summarised many of the currently licenced influenza vaccines available across the world and current vaccines in clinical trials. We then briefly discuss the important role of CD8⁺ T cells during influenza infection and why future influenza vaccines should consider targeting CD8⁺ T cells. Finally, we assess the current landscape of known immunogenic CD8⁺ T-cell epitopes and highlight the knowledge gaps required to be filled for the design of rational future influenza vaccines that incorporate CD8⁺ T cells.</p>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139739129","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":"Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies placental dysfunction signatures","authors":"Nataly Stylianou,&nbsp;Ismail Sebina,&nbsp;Nicholas Matigian,&nbsp;James Monkman,&nbsp;Hadeel Doehler,&nbsp;Joan Röhl,&nbsp;Mark Allenby,&nbsp;Andy Nam,&nbsp;Liuliu Pan,&nbsp;Anja Rockstroh,&nbsp;Habib Sadeghirad,&nbsp;Kimberly Chung,&nbsp;Thais Sobanski,&nbsp;Ken O'Byrne,&nbsp;Ana Clara Simoes Florido Almeida,&nbsp;Patricia Zadorosnei Rebutini,&nbsp;Cleber Machado-Souza,&nbsp;Emanuele Therezinha Schueda Stonoga,&nbsp;Majid E Warkiani,&nbsp;Carlos Salomon,&nbsp;Kirsty Short,&nbsp;Lana McClements,&nbsp;Lucia de Noronha,&nbsp;Ruby Huang,&nbsp;Gabrielle T Belz,&nbsp;Fernando Souza-Fonseca-Guimaraes,&nbsp;Vicki Clifton,&nbsp;Arutha Kulasinghe","doi":"10.1002/cti2.1488","DOIUrl":"10.1002/cti2.1488","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a ‘preeclampsia-like syndrome’. However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We utilised whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (<i>n</i> = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (<i>n</i> = 9).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS-CoV-2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (<i>NOS3</i>), oxidative stress (<i>GDF15</i>, <i>CRH</i>) and preeclampsia (<i>FLT1</i>, <i>EGFR</i>, <i>KISS1</i>, <i>PAPPA2</i>) were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS-CoV-2 samples compared to uninfected controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10846628/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696582","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":"Infiltrating characteristics and prognostic value of tertiary lymphoid structures in resected gastric neuroendocrine neoplasm patients","authors":"Daming Cai,&nbsp;Xingzhou Wang,&nbsp;Heng Yu,&nbsp;Chunhua Bai,&nbsp;Yonghuan Mao,&nbsp;Mengjie Liang,&nbsp;Xuefeng Xia,&nbsp;Song Liu,&nbsp;Meng Wang,&nbsp;Xiaofeng Lu,&nbsp;Junfeng Du,&nbsp;Xiaofei Shen,&nbsp;Wenxian Guan","doi":"10.1002/cti2.1489","DOIUrl":"https://doi.org/10.1002/cti2.1489","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Tertiary lymphoid structures (TLSs) are lymphocyte aggregates that play an anti-tumor role in most solid tumors. However, the functions of TLS in gastric neuroendocrine neoplasms (GNENs) remain unknown. This study aimed to determine the characteristics and prognostic values of TLS in resected GNEN patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Haematoxylin–eosin, immunohistochemistry (IHC) and multiple fluorescent IHC staining were used to assess TLS to investigate the correlation between TLSs and clinicopathological characteristics and its prognostic value.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Tertiary lymphoid structures were identified in 84.3% of patients with GNEN. They were located in the stromal area or outside the tumor tissue and mainly composed of B and T cells. A high density of TLSs promoted an anti-tumor immune response in GNEN. CD15⁺ TANs and FOXP3⁺ Tregs in TLSs inhibited the formation of TLSs. High TLS density was significantly associated with prolonged recurrence-free survival (RFS) and overall survival (OS) of GNENs. Univariate and multivariate Cox regression analyses revealed that TLS density, tumor size, tumor–node–metastasis (TNM) stage and World Health Organisation (WHO) classification were independent prognostic factors for OS, whereas TLS density, tumor size and TNM stage were independent prognostic factors for RFS. Finally, OS and RFS nomograms were developed and validated, which were superior to the WHO classification and the TNM stage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Tertiary lymphoid structures were mainly located in the stromal area or outside the tumor area, and high TLS density was significantly associated with the good prognosis of patients with GNEN. Incorporating TLS density into a nomogram may improve survival prediction in patients with resected GNEN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1489","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139695182","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":"SARS-CoV-2-associated T-cell infiltration in the central nervous system","authors":"Malte Mohme,&nbsp;Christoph Schultheiß,&nbsp;Andras Piffko,&nbsp;Antonia Fitzek,&nbsp;Lisa Paschold,&nbsp;Benjamin Thiele,&nbsp;Klaus Püschel,&nbsp;Markus Glatzel,&nbsp;Manfred Westphal,&nbsp;Katrin Lamszus,&nbsp;Jakob Matschke,&nbsp;Mascha Binder","doi":"10.1002/cti2.1487","DOIUrl":"10.1002/cti2.1487","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). Although an acute SARS-CoV-2 infection mainly presents with respiratory illness, neurologic symptoms and sequelae are increasingly recognised in the long-term treatment of COVID-19 patients. The pathophysiology and the neuropathogenesis behind neurologic complications of COVID-19 remain poorly understood, but mounting evidence points to endothelial dysfunction either directly caused by viral infection or indirectly by inflammatory cytokines, followed by a local immune response that may include virus-specific T cells. However, the type and role of central nervous system-infiltrating T cells in COVID-19 are complex and not fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed distinct anatomical brain regions of patients who had deceased as a result of COVID-19-associated pneumonia or complications thereof and performed T cell receptor Vβ repertoire sequencing. Clonotypes were analysed for SARS-CoV-2 association using public TCR repertoire data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our descriptive study demonstrates that SARS-CoV-2-associated T cells are found in almost all brain areas of patients with fatal COVID-19 courses. The olfactory bulb, medulla and cerebellum were brain regions showing the most SARS-CoV-2 specific sequence patterns. Neuropathological workup demonstrated primary CD8⁺ T-cell infiltration with a perivascular infiltration pattern.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Future research is needed to better define the relationship between T-cell infiltration and neurological symptoms and its long-term impact on patients' cognitive and mental health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1487","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657271","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":"γδ T cells mediate robust anti-HIV functions during antiretroviral therapy regardless of immune checkpoint expression","authors":"Kirsty R Field,&nbsp;Kathleen M Wragg,&nbsp;Stephen J Kent,&nbsp;Wen Shi Lee,&nbsp;Jennifer A Juno","doi":"10.1002/cti2.1486","DOIUrl":"https://doi.org/10.1002/cti2.1486","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Although antiretroviral therapy (ART) efficiently suppresses HIV viral load, immune dysregulation and dysfunction persist in people living with HIV (PLWH). γδ T cells are functionally impaired during untreated HIV infection, but the extent to which they are reconstituted upon ART is currently unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Utilising a cohort of ART-treated PLWH, we assessed the frequency and phenotype, characterised <i>in vitro</i> functional responses and defined the impact of immune checkpoint marker expression on effector functions of both Vδ1 and Vδ2 T cells. We additionally explore the <i>in vitro</i> expansion of Vδ2 T cells from PLWH on ART and the mechanisms by which such expanded cells may sense and kill HIV-infected targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A matured NK cell-like phenotype was observed for Vδ1 T cells among 25 ART-treated individuals (PLWH/ART) studied compared to 17 HIV-uninfected controls, with heightened expression of 2B4, CD160, TIGIT and Tim-3. Despite persistent phenotypic perturbations, Vδ1 T cells from PLWH/ART exhibited strong CD16-mediated activation and degranulation, which were suppressed upon Tim-3 and TIGIT crosslinking. Vδ2 T cell degranulation responses to the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate at concentrations up to 2 ng mL⁻¹ were significantly impaired in an immune checkpoint-independent manner among ART-treated participants. Nonetheless, expanded Vδ2 T cells from PLWH/ART retained potent anti-HIV effector functions, with the NKG2D receptor contributing substantially to the elimination of infected cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings highlight that although significant perturbations remain within the γδ T cell compartment throughout ART-treated HIV, both subsets retain the capacity for robust anti-HIV effector functions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 2","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1486","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139643901","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":"Multi-omics integration reveals a nonlinear signature that precedes progression of lung fibrosis","authors":"Céline Pattaroni,&nbsp;Christina Begka,&nbsp;Bailey Cardwell,&nbsp;Jade Jaffar,&nbsp;Matthew Macowan,&nbsp;Nicola L Harris,&nbsp;Glen P Westall,&nbsp;Benjamin J Marsland","doi":"10.1002/cti2.1485","DOIUrl":"10.1002/cti2.1485","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Idiopathic pulmonary fibrosis (IPF) is a devastating progressive interstitial lung disease with poor outcomes. While decades of research have shed light on pathophysiological mechanisms associated with the disease, our understanding of the early molecular events driving IPF and its progression is limited. With this study, we aimed to model the leading edge of fibrosis using a data-driven approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Multiple omics modalities (transcriptomics, metabolomics and lipidomics) of healthy and IPF lung explants representing different stages of fibrosis were combined using an unbiased approach. Multi-Omics Factor Analysis of datasets revealed latent factors specifically linked with established fibrotic disease (Factor1) and disease progression (Factor2).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Features characterising Factor1 comprised well-established hallmarks of fibrotic disease such as defects in surfactant, epithelial–mesenchymal transition, extracellular matrix deposition, mitochondrial dysfunction and purine metabolism. Comparatively, Factor2 identified a signature revealing a nonlinear trajectory towards disease progression. Molecular features characterising Factor2 included genes related to transcriptional regulation of cell differentiation, ciliogenesis and a subset of lipids from the endocannabinoid class. Machine learning models, trained upon the top transcriptomics features of each factor, accurately predicted disease status and progression when tested on two independent datasets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This multi-omics integrative approach has revealed a unique signature which may represent the inflection point in disease progression, representing a promising avenue for the identification of therapeutic targets aimed at addressing the progressive nature of the disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"13 1","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10807351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139544817","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}