دورية أكاديمية
Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis
| العنوان: | Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis |
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| المؤلفون: | Slevin, Stephanie M, Garner, Lucy C, Lahiff, Conor, Tan, Malcolm, Wang, Lai Mun, Ferry, Helen, Greenaway, Borgel, Lynch, Kate, Geremia, Alessandra, Hughes, Stephen, Leavens, Karen, Krull, David, Marks, Daniel J B, Nevin, Katherine, Page, Kevin, Srinivasan, Naren, Tarzi, Ruth, Klenerman, Paul, Travis, Simon, Arancibia-Cárcamo, Carolina V, Keshav, Satish |
| المساهمون: | GlaxoSmithKline, Wellcome Trust, NIHR Oxford Biomedical Research Centre |
| المصدر: | Journal of Crohn's and Colitis ; volume 14, issue 10, page 1446-1461 ; ISSN 1873-9946 1876-4479 |
| بيانات النشر: | Oxford University Press (OUP) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Gastroenterology, General Medicine |
| الوصف: | Background and Aims Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. Methods The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. Results LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. Conclusions LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1093/ecco-jcc/jjaa054 |
| DOI: | 10.1093/ecco-jcc/jjaa054/33131000/jjaa054.pdf |
| الإتاحة: | https://doi.org/10.1093/ecco-jcc/jjaa054Test http://academic.oup.com/ecco-jcc/article-pdf/14/10/1446/33835501/jjaa054.pdfTest |
| حقوق: | http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.AD44A279 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/ecco-jcc/jjaa054 |
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