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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.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lag-3-regulatory-t-cells-suppress-effector-function-of-t-cells-and-allow-their-proliferation-into-regulatory-t-cells/456720/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lag-3-regulatory-t-cells-suppress-effector-function-of-t-cells-and-allow-their-proliferation-into-regulatory-t-cells/456720.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What effect do LAG-3+ regulatory T cells have on antigen-specific CD4+ T cell responses in vivo?","Question",{"text":113,"@type":114},"They suppress the effector function of naïve cognate antigen-specific CD4+ T cells while not suppressing their proliferative response in vivo.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which molecular pathways and checkpoints are altered in suppressed CD4+ T cells?",{"text":118,"@type":114},"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.",{"name":120,"@type":111,"acceptedAnswer":121},"How do LAG-3+ aTreg cells perform after adoptive transfer in the mouse autoimmune pulmonitis model?",{"text":122,"@type":114},"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.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},456720,1790789887,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":41,"preview_page_count":4},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","Immunology  \nORIGINAL ARTICLE  OPEN ACCESS   \nLAG-3+ Regulatory T Cells Suppress Effector Function ofT Cells and Allow Their Proliferation Into Regulatory T Cells  \nAvijit 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  \n1AMITY 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  \nCorrespondence: Ching-Tai Huang ([chingtaihuang@gmail.com](chingtaihuang@gmail.com))  \nReceived: 25 April 2025 | Revised: 13 August 2025 | Accepted: 24 September 2025  \nFunding: 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.  \nKeywords: effector function-suppressed proliferation | hemagglutinin-specific CD4+ T cells | infectious tolerance | LAG-3+ aTreg cell  \nABSTRACT  \nLAG-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.  \n1 | Introduction  \nImmune 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  \ncells (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.  \nThis 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.  \n© 2025 The Author(s). Immunology published by John","cbCaifEk7dwR5yyh","https://ap.wps.com/l/cbCaifEk7dwR5yyh","pdf",4895226,12,"English","# Introduction\n## Role of immune tolerance and adaptive Treg\n# Results\n## LAG-3+ aTreg cells suppress effector function and allow proliferation in vivo","[{\"question\":\"What effect do LAG-3+ regulatory T cells have on antigen-specific CD4+ T cell responses in vivo?\",\"answer\":\"They suppress the effector function of naïve cognate antigen-specific CD4+ T cells while not suppressing their proliferative response in vivo.\"},{\"question\":\"Which molecular pathways and checkpoints are altered in suppressed CD4+ T cells?\",\"answer\":\"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.\"},{\"question\":\"How do LAG-3+ aTreg cells perform after adoptive transfer in the mouse autoimmune pulmonitis model?\",\"answer\":\"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.\"}]","LAG-3+ Regulatory T Cells Suppress Effector Function of T Cells and Allow Their Proliferation Into Regulatory T Cells | PDF",1790746782]