Genetic determination of T cell help in loss of tolerance to nuclear antigens.
Sle1 is a major lupus susceptibility locus in NZM2410 lupus model that is associated with a loss of tolerance to nuclear Ags. At least three genes, Sle1a, Sle1b, and Sle1c contribute to Sle1, and their relative role in lupus pathogenesis is unknown. We show here that Sle1-expressing CD4(+) T cells present an activated phenotype associated with increased proliferation and cytokine production. In addition, Sle1 CD4(+) T cells provide help to anti-chromatin B cells to produce anti-nuclear antibodies, whether or not these B cells express Sle1. The Sle1a locus alone accounts for all these Sle1 phenotypes, implying that a specific genetic defect in Sle1a is necessary and sufficient to produce autoreactive T cells. However, Sle1c induces intermediate T cell activation and only provides help to Sle1-expressing anti-chromatin-producing B cells, demonstrating the synergic interactions between Sle1c T and Sle1 B cells. Moreover, Sle1a and Sle1c were associated with a significantly reduced level of CD4(+)CD25(+) regulatory T cells that precedes autoantibody production, suggesting a causal relationship with the generation of autoreactive T cells. Our study identifies for the first time that a specific genetic defect is responsible for lupus pathogenesis by inducing autoreactive T cells to break self-tolerance and that this genetic defect is also associated with a decreased number of regulatory T cells.
Chen
Yifang
Y
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
Cuda
Carla
C
Morel
Laurence
L
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D034961:Antigens, Nuclear / Q000276:immunology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002843:Chromatin / Q000276:immunology; D002874:Chromosome Mapping; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics*; D007074:Immunoglobulin G / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D000974:Antibodies, Antinuclear; D034961:Antigens, Nuclear; D002843:Chromatin; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006657:Histones; D007074:Immunoglobulin G