The amount of self-antigen determines the effector function of murine T cells escaping negative selection.
Autoimmune diseases develop when self-specific T cells that escaped negative selection initiate a harmful immune response against self. However, factors, which influence the initiation and progression of an autoimmune response remain incompletely understood. By establishing a double-transgenic BALB/c mouse system in which different amounts of a cell-surface neo-self-antigen are expressed under the CD11c promoter, we demonstrate that antigen dose dramatically influences T-cell tolerance mechanisms. Moderate antigen expression in both hematopoietic and nonhematopoietic cells favors the development of antigen-specific Treg cells and the establishment of a tolerogenic environment. In marked contrast, a high dose of antigen expression results in very stringent negative selection, in poor development of antigen-specific Treg cells and in the early onset of anemia and splenomegaly and the late development of arthritis and high titers of IgG auto Abs. Disease is initiated by autoreactive T cells, which escape negative selection by expressing a second TCR with a different specificity or an altered affinity. Transfer of Ag-specific Treg cells ameliorates the early onset signs of disease but does not prevent the development of long-term chronic pathologies. Altogether, our results suggest that Ag dose directly affects Treg-cell generation and thus, the set-up of T-cell tolerance.
Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Lee K
LK
Swee
Anja
A
Nusser
Maurus
M
Curti
Matthias
M
Kreuzaler
Hannie
H
Rolink
Luigi
L
Terracciano
Fritz
F
Melchers
Jan
J
Andersson
Antonius
A
Rolink
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001324:Autoantigens / Q000097:blood / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D039521:CD11c Antigen / Q000097:blood / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D001324:Autoantigens; D039521:CD11c Antigen; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell
Avidity; T cells; Tolerance; Treg-cell development