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

Britta E. Jones, Megan D. Maerz, Henry T. Bahnson, Ashwin Somasundaram, Lucas H. McCarthy, Cate Speake and Jane H. Buckner
J Immunol February 1, 2022, 208 (3) 594-602; DOI: https://doi.org/10.4049/jimmunol.2100850
Britta E. Jones
*Translational Research Program, Benaroya Research Institute, Seattle, WA;
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Megan D. Maerz
†Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA;
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Henry T. Bahnson
‡Center for Interventional Immunology, Benaroya Research Institute, Seattle, WA; and
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Ashwin Somasundaram
§Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Lucas H. McCarthy
‡Center for Interventional Immunology, Benaroya Research Institute, Seattle, WA; and
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Cate Speake
‡Center for Interventional Immunology, Benaroya Research Institute, Seattle, WA; and
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Jane H. Buckner
*Translational Research Program, Benaroya Research Institute, Seattle, WA;
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Key Points

  • There are fewer LAG-3+ CD4 and CD8 T cells in subjects with RRMS and T1D.

  • LAG-3 protein expression is linked to alterations in mRNA expression.

  • Low LAG-3 may be associated with a decrease in T cell death in subjects with RRMS.

Abstract

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.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant R01 AI132774 to J.H.B.).

  • B.E.J. and J.H.B. conceived the project and designed the experiments. B.E.J. performed the experiments, analyzed the data, prepared the figures, and wrote the manuscript. M.D.M. assisted in conducting experiments and reviewed the article. H.T.B. was the consulting statistician. A.S. developed the technique for intracellular LAG-3 staining by flow cytometry, provided guidance on experimental design, and reviewed the article. L.H.M. and C.S. are the clinical principal investigators responsible for Neurology and Diabetes sample repositories. J.H.B. oversaw the project and reviewed the article.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    cCasp3
    cleaved caspase 3
    DMT
    disease-modifying therapy
    EAE
    experimental autoimmune encephalomyelitis
    gMFI
    geometric mean fluorescence intensity
    HC
    healthy control subject
    IR
    inhibitory receptor
    LAG-3
    lymphocyte activation gene-3
    LAG-3NC
    noncleavable lymphocyte activation gene-3
    MS
    multiple sclerosis
    RRMS
    relapsing-remitting multiple sclerosis
    sLAG3
    soluble LAG-3
    TAPI-1
    TNF-α protease inhibitor-1
    T1D
    type 1 diabetes

  • Received August 26, 2021.
  • Accepted November 23, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (3)
The Journal of Immunology
Vol. 208, Issue 3
1 Feb 2022
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Fewer LAG-3+ T Cells in Relapsing-Remitting Multiple Sclerosis and Type 1 Diabetes
Britta E. Jones, Megan D. Maerz, Henry T. Bahnson, Ashwin Somasundaram, Lucas H. McCarthy, Cate Speake, Jane H. Buckner
The Journal of Immunology February 1, 2022, 208 (3) 594-602; DOI: 10.4049/jimmunol.2100850

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Fewer LAG-3+ T Cells in Relapsing-Remitting Multiple Sclerosis and Type 1 Diabetes
Britta E. Jones, Megan D. Maerz, Henry T. Bahnson, Ashwin Somasundaram, Lucas H. McCarthy, Cate Speake, Jane H. Buckner
The Journal of Immunology February 1, 2022, 208 (3) 594-602; DOI: 10.4049/jimmunol.2100850
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