Rosemarie Faustina Le

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by neuroinflammation, demyelination, and neurodegeneration which collectively lead to significant physical and cognitive disabilities.^1-3 Currently, 2.9 million people worldwide live with MS with the highest prevalence found in Europe and the Americas.^1-3 The disease most commonly affects young females, typically diagnosed around the age of 32, and presents with symptoms such as optic neuritis, fatigue, and motor deficits.^1-3 While the exact etiology remains unknown, the leading paradigm of MS pathogenesis involves a critical imbalance: the activation of pro-inflammatory Th1, Th17, and B cells against oligodendrocyte antigens alongside a decrease in anti-inflammatory T regulatory (Treg) lymphocytes.^1,2,4 Existing disease-modifying therapies (DMTs) manage the disease by modulating immune activity to reduce relapses, but they often induce global immunosuppression and fail to halt the underlying neurodegeneration.^1-3 There is an urgent clinical need for “precision” therapies that can restore immune tolerance without compromising the patient’s overall immune competence.^1-3 The objective of this literature review is to evaluate the efficacy and potential of engineered antigen-specific Tregs –including those modified with T-cell receptors (TCRs) and chimeric antigen receptors (CARs)– to restore peripheral tolerance and improve clinical outcomes in MS models.

Search Methods: A comprehensive literature search was conducted using PubMed for studies published between 2017 and 2025. Search strategies utilized the MeSH terms  “Multiple Sclerosis,” “T-Lymphocytes, Regulatory,” and “Immune Tolerance” or “Immunosuppression Therapy”.

Results: Research indicates that engineered Tregs can effectively target myelin antigens and induce localized immunosuppression.⁵ Initial proof-of-concept studies demonstrated that TCR-engineered Tregs specific for myelin basic protein (MBP) could suppress MBP-specific T effector cell proliferation in vitro more effectively than control Tregs.⁵ In vivo experiments using experimental autoimmune encephalomyelitis mouse models showed these MBP-specific Tregs successfully infiltrated the CNS and significantly reduced mean disease scores.⁵ To address the “HLA-restriction” limitations of TCR-based therapies as they require compatible Major Histocompatibility Complex (MHC) presentation, subsequent research turned to CAR Tregs.^6-7 CARs utilize a single-chain variable antibody fragment (scFv) to bind antigens independently of MHC, allowing for broader “off-the-shelf” utility.^6-7 MOG-specific CAR Tregs have been shown to maintain a stable FoxP3⁺ and Helios⁺ phenotype even after expansion.⁷ These CAR Tregs migrate specifically to the CNS where they exert multi-layered suppressive effects, including inhibiting dendritic cell maturation and decreasing the number of CD4⁺ T cells producing IFN-γ.^6-7 Furthermore, studies on bi-specific Tregs and “contact-independent bystander suppression” suggest that targeting a single dominant epitope can provide protection against the multi-antigenic attacks seen in late-stage MS, where the primary target antigen may be unclear.^5,8

Conclusion: Engineered myelin-specific Tregs represent a promising alternative to broad immunosuppression by targeting only the pathogenic autoimmune response. Despite these advancements, significant challenges remain regarding the long-term phenotypic stability of Tregs, as they may convert into pro-inflammatory “ex-Tregs” under high inflammatory conditions.^5,7,8 Future research must address the scalability of manufacturing, the development of delivery methods for sustained therapeutic presence, and the long-term durability of immune tolerance in humans.

Works Cited

1. Lorenzut S, Negro ID, Pauletto G, et al. Exploring the Pathophysiology, Diagnosis, and Treatment Options of Multiple Sclerosis. J Integr Neurosci. 2025;24(1):25081. doi:10.31083/JIN25081
2. Boutitah-Benyaich I, Eixarch H, Villacieros-Álvarez J, et al. Multiple sclerosis: molecular pathogenesis and therapeutic intervention. Sig Transduct Target Ther. 2025;10(1):324. doi:10.1038/s41392-025-02415-4
3. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology. 2018;17(2):162-173. doi:10.1016/S1474-4422(17)30470-2
4. Gupta S, Simic M, Sagan SA, et al. CAR-T Cell–Mediated B-Cell Depletion in Central Nervous System Autoimmunity. Neurol Neuroimmunol Neuroinflamm. 2023;10(2):e200080. doi:10.1212/NXI.0000000000200080
5. Kim YC, Zhang AH, Yoon J, et al. Engineered MBP-specific human Tregs ameliorate MOG-induced EAE through IL-2-triggered inhibition of effector T cells. Journal of Autoimmunity. 2018;92:77-86. doi:10.1016/j.jaut.2018.05.003
6. De Paula Pohl A, Schmidt A, Zhang AH, Maldonado T, Königs C, Scott DW. Engineered regulatory T cells expressing myelin-specific chimeric antigen receptors suppress EAE progression. Cellular Immunology. 2020;358:104222. doi:10.1016/j.cellimm.2020.104222
7. Frikeche J, David M, Mouska X, et al. MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis. J Neuroinflammation. 2024;21(1):268. doi:10.1186/s12974-024-03262-w
8. Malviya M, Saoudi A, Bauer J, Fillatreau S, Liblau R. Treatment of experimental autoimmune encephalomyelitis with engineered bi-specific Foxp3+ regulatory CD4+ T cells. Journal of Autoimmunity. 2020;108:102401. doi:10.1016/j.jaut.2020.102401