Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance.
CD4+ helper T cells play a critical role in the production of the antinuclear autoantibodies that characterize systemic lupus erythematosus in mice and humans. A key issue is whether this help is derived from a diverse repertoire of autoreactive CD4+ T cells or from a select number of T cells of limited specificity. We used the chronic graft-versus-host disease model to define the diversity of the CD4+ T cell repertoire required to induce the autoantibody response. By transferring clonally restricted versus clonally diverse populations of MHC class II-reactive CD4+ T cells, we show that the loss of B cell tolerance to nuclear antigens has two distinct components with different CD4+ cell requirements. Activation of limited repertoires of CD4+ T cells was sufficient for the expansion of anergized anti-double-stranded DNA B cells and production of IgM autoantibodies. Unexpectedly, we found that CD4+ T cell diversity was necessary for CD4+ T cell trafficking into the follicle and for the generation of isotype-switched IgG autoantibodies. Importantly, combining two limited repertoires of T cells provides sufficient CD4+ T cell diversity to drive antinuclear Ab production. These data demonstrate that a diverse CD4+ T cell repertoire is required to generate a sustained effector B cell response capable of mediating systemic autoimmunity.
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. tlaufer@mail.med.upenn.edu
Brian W
BW
Busser
Brigette S
BS
Adair
Jan
J
Erikson
Terri M
TM
Laufer
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology*; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002843:Chromatin / Q000276:immunology; D002908:Chronic Disease; D004247:DNA / Q000276:immunology*; D006086:Graft vs Host Disease; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000209:etiology; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D002843:Chromatin; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D004247:DNA