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.
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
Log in using your username and password
In this issue
