LAG-3+ Regulatory T Cells Suppress Effector Function of T Cells and Allow Their Proliferation Into Regulatory T Cells

Sep 30, 2026

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LAG-3+ regulatory T cells suppress effector responses while preserving the proliferative capacity of naïve, cognate antigen-specific CD4+ T cells in vivo. The Th1, Th2, and Th17 programs in suppressed CD4+ T cells are disrupted, with genomic signatures showing enhanced TCR signaling, increased immune checkpoint expression (PD-1/PD-L1), and reduced pro-inflammatory pathways. Despite reduced oxidative metabolism, suppressed T cells retain proliferation, up-regulate LAG-3, and acquire LAG-3+ regulatory features, inhibit co-cultured IFN-γ responses, and—after adoptive transfer—rescue mice from lethal autoimmune pulmonitis in a dose-dependent manner. These findings support a mechanism for long-lasting antigen-specific tolerance.

LanguageEnglish

CategoryHealthcare

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Introduction

Role of immune tolerance and adaptive Treg

Results

LAG-3+ aTreg cells suppress effector function and allow proliferation in vivo

Immunology ORIGINAL ARTICLE OPEN ACCESS LAG-3+ Regulatory T Cells Suppress Effector Function ofT Cells and Allow Their Proliferation Into Regulatory T Cells Avijit Dutta1,2,3 | Shi-Chuen Miaw4 | Tse-Ching Chen5,6 | Chia-Shiang Chang3 | Yu-Lin Huang3 | Yung-Chang Lin6,7 | Chun-Yen Lin6,8 | Ching-Tai Huang3,6 1AMITY Institute of Virology and Immunology, AMITY University Uttar Pradesh, Noida, India | 2Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan | 3Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan | 4Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan | 5Department of Pathology, Chang Gung Memorial Hospital, Taoyuan, Taiwan | 6College of Medicine, Chang Gung University, Taoyuan, Taiwan | 7Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan | 8Division of Hepatogastroenterology, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan Correspondence: Ching-Tai Huang ([chingtaihuang@gmail.com](chingtaihuang@gmail.com)) Received: 25 April 2025 | Revised: 13 August 2025 | Accepted: 24 September 2025 Funding: This work was supported by Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan, CMRPG3M1031-2, CMRPG3M1811; Ministry of Education (MOE) Taiwan; National Science and Technology Council Taiwan, 112-2314-B-182A-041-MY3, NSTC-111-2314-B-182-029. Keywords: effector function-suppressed proliferation | hemagglutinin-specific CD4+ T cells | infectious tolerance | LAG-3+ aTreg cell ABSTRACT LAG-3+ regulatory T cells suppress the effector but not the proliferative response of naïve cognate antigen-specific CD4+ T cells in vivo. The Th1, Th2, and Th17 machineries in the suppressed CD4+ T cells are impaired. Genomic study of the suppressed T cells revealed enhanced T cell receptor signalling with up-regulation of immune checkpoints, including PD-1 and PD-L1, and down-regulation of pro-inflammatory pathways. Although oxidative metabolism is reduced, the suppressed T cells retain proliferative capacity and acquire LAG-3 expression with proliferation. They acquire the capacity of LAG-3+ regulatory T cells. They inhibit the IFN-γ response of co-cultured naïve CD4+ T cells in vitro. Upon adoptive transfer, they rescue mice from lethal autoimmune pulmonitis in a dose-dependent manner. Our results implied a mechanism for the maintenance of long-lasting antigen-specific tolerance. 1 | Introduction Immune tolerance refers to a state in which the immune system does not respond to specific antigens. Most self-reactive T cells undergo negative selection and are eliminated in the process of maturation in the thymus to prevent autoimmune reactions [1] . Self-reactive T cells may mature and develop into regulatory T (Treg) cells in the thymus and emigrate to the periphery to secure tolerance to self-antigens [2–4] . Mature T cells may also be induced in the periphery to be adaptive Treg cells (aTreg) to maintain tolerance to antigens such as those of cancer or chronic infections [5–7] . Engagement of inhibitory receptors, the immune checkpoints, such as CTLA-4, PD-1, or LAG-3, on Treg cell surface is essential for their function [8–12] . Monoclonal antibodies targeting immune checkpoints reverse aTreg-mediated immune tolerance and have been utilised successfully in immune oncology for the treatment of cancers [12, 13]. However, improvement for better treatment outcomes is still desired, and mechanisms for unsatisfactory treatment need further investigation. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2025 The Author(s). Immunology published by John

FAQs

What effect do LAG-3+ regulatory T cells have on antigen-specific CD4+ T cell responses in vivo?

They suppress the effector function of naïve cognate antigen-specific CD4+ T cells while not suppressing their proliferative response in vivo.

Which molecular pathways and checkpoints are altered in suppressed CD4+ T cells?

Suppressed T cells show impaired Th1/Th2/Th17 machinery, enhanced TCR signaling with up-regulation of immune checkpoints (including PD-1 and PD-L1), and down-regulation of pro-inflammatory pathways.

How do LAG-3+ aTreg cells perform after adoptive transfer in the mouse autoimmune pulmonitis model?

After adoptive transfer, they rescue mice from lethal autoimmune pulmonitis in a dose-dependent manner and inhibit IFN-γ responses of co-cultured naïve CD4+ T cells in vitro.

Sep 30, 2026

Uploaded by Patrick