Fewer LAG-3+ T Cells in Relapsing-Remitting Multiple Sclerosis and Type 1 Diabetes

The coinhibitory receptor lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates T cell activation, proliferation, and homeostasis. Blockade or deletion of LAG-3 in autoimmune-prone backgrounds or induced-disease models has been shown to exacerbate disease. W...

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Published inThe Journal of immunology (1950) Vol. 208; no. 3; pp. 594 - 602
Main Authors Jones, Britta E., Maerz, Megan D., Bahnson, Henry T., Somasundaram, Ashwin, McCarthy, Lucas H., Speake, Cate, Buckner, Jane H.
Format Journal Article
LanguageEnglish
Published United States 01.02.2022
Subjects
Antigens, CD - metabolism
Apoptosis - physiology
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Cell Proliferation - physiology
Diabetes Mellitus, Type 1 - immunology
Gene Expression Regulation - genetics
Humans
Lymphocyte Activation - immunology
Lymphocyte Activation Gene 3 Protein
Multiple Sclerosis, Relapsing-Remitting - immunology
RNA, Messenger - biosynthesis
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Summary:The coinhibitory receptor lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates T cell activation, proliferation, and homeostasis. Blockade or deletion of LAG-3 in autoimmune-prone backgrounds or induced-disease models has been shown to exacerbate disease. We observed significantly fewer LAG-3+ CD4 and CD8 T cells from subjects with relapsing-remitting multiple sclerosis (RRMS) and type 1 diabetes. Low LAG-3 protein expression was linked to alterations in mRNA expression and not cell surface cleavage. Functional studies inhibiting LAG-3 suggest that in subjects with RRMS, LAG-3 retains its ability to suppress T cell proliferation. However, LAG-3 expression was associated with the expression of markers of apoptosis, indicating a role for low LAG-3 in T cell resistance to cell death. In T cells from subjects with RRMS, we observed a global dysregulation of LAG-3 expression stemming from decreased transcription and persisting after T cell stimulation. These findings further support the potential clinical benefits of a LAG-3 agonist in the treatment of human autoimmunity.
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BEJ and JHB conceived the project and designed the experiments. BEJ performed the experiments, analyzed the data, prepared the figures, and wrote the manuscript. MDM assisted in conducting experiments and reviewed the article. HTB was the consulting statistician. AS developed the technique for intracellular LAG-3 staining by flow cytometry, provided guidance on experimental design, and reviewed the article. LHM and CS are the clinical PIs responsible for Neurology and Diabetes sample repositories. JHB oversaw the project and reviewed the article. The authors declare no conflicts of interest in relation to this manuscript.
Author contributions
ISSN:0022-1767
1550-6606
1550-6606
DOI:10.4049/jimmunol.2100850