title: Antigen dynamics govern the induction of CD4(+) T cell tolerance during autoimmunity.
abstract: Antigen-specific T cell tolerance holds great promise for the treatment of autoimmune diseases. However, strategies to induce durable tolerance using high doses of soluble antigen have to date been unsuccessful, due to lack of efficacy and the risk of hypersensitivity. In the current study we have overcome these limitations by developing a platform for tolerance induction based on engineering the immunoglobulin Fc region to modulate the dynamic properties of low doses (1 μg/mouse; ∼50 μg/kg) of Fc-antigen fusions. Using this approach, we demonstrate that antigen persistence is a dominant factor governing the elicitation of tolerance in the model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), induced by immunizing B10.PL mice with the N-terminal epitope of myelin basic protein. Unexpectedly, our analyses reveal a stringent threshold of antigen persistence for both prophylactic and therapeutic treatments, although distinct mechanisms lead to tolerance in these two settings. Importantly, the delivery of tolerogenic Fc-antigen fusions during ongoing disease results in the downregulation of T-bet and CD40L combined with amplification of Foxp3(+) T cell numbers. The generation of effective, low dose tolerogens using Fc engineering has potential for the regulation of autoreactive T cells.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, 469 Joe H. Reynolds Medical Sciences Building, 1114 TAMU, College Station, TX 77843, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Challa
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Wentao
authors.initials: W
authors.lastname: Mi
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA.
authors.forename: Su-Tang
authors.initials: ST
authors.lastname: Lo
authors.affiliation: Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, 469 Joe H. Reynolds Medical Sciences Building, 1114 TAMU, College Station, TX 77843, USA; Department of Biomedical Engineering, Texas A&M University, 5045 Emerging Technologies Building, 3120 TAMU, College Station, TX 77843, USA.
authors.forename: Raimund J
authors.initials: RJ
authors.lastname: Ober
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390, USA; Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M Health Science Center, 469 Joe H. Reynolds Medical Sciences Building, 1114 TAMU, College Station, TX 77843, USA; Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, 3107 Medical Research & Education Building, 8447 State Hwy 47, Bryan, TX 77807, USA. Electronic address: sally.ward@medicine.tamhsc.edu.
authors.forename: E Sally
authors.initials: ES
authors.lastname: Ward
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D000939:Epitopes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D008297:Male; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000517:prevention & control; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000941:Antigens; D000939:Epitopes; D007141:Immunoglobulin Fc Fragments; D004676:Myelin Basic Protein; D011993:Recombinant Fusion Proteins
keywords: Autoimmunity; CD4(+) T cells; EAE; Fc engineering; FcRn; Tolerance