Human double-negative T cells in systemic lupus erythematosus provide help for IgG and are restricted by CD1c.
To understand the mechanism of T cell help for IgG production in systemic lupus erythematosus (SLE) we investigated the response of CD4- and CD8-negative (double-negative (DN)) T cells because 1) DN T cells are present at unusually high frequency in patients with SLE and can induce pathogenic autoantibodies; 2) the DN T cell repertoire includes cells restricted by CD1 Ag-presenting molecules; and 3) CD1c is expressed on a population of circulating B cells. We derived DN T cell lines from SLE patients and healthy individuals. In the presence of CD1(+) APCs, DN T cell lines from SLE patients produced both IL-4 and IFN-gamma, whereas DN T cells from healthy donors produced IFN-gamma, but no IL-4. In general, cells from patients with highly active disease produced high levels of IFN-gamma; cells from those with little activity produced high IL-4. Coculture of CD1c-directly reactive T cells from healthy donors with CD1c(+) B cells elicited IgM Abs, but little or no IgG. In contrast, CD1c-directly reactive T cells from SLE patients induced isotype switching, with a striking increase in IgG production. Neutralizing Abs to CD1c inhibited the ability of DN T cells to induce IgG production from CD1c(+) B cells, further indicating that CD1c mediated the T and B cell interaction. IgG production was also inhibited by neutralizing Abs to IL-4, correlating with the cytokine pattern of DN T cells derived from these patients. The data suggest that CD1c-restricted T cells from SLE patients can provide help to CD1c(+) B cells for IgG production and could therefore promote pathogenic autoantibody responses in SLE.
Sieling
P A
PA
Division of Dermatology and Rheumatology, University of California School of Medicine, Los Angeles, CA 90095, USA. psieling@mednet.ucla.edu
Porcelli
S A
SA
Duong
B T
BT
Spada
F
F
Bloom
B R
BR
Diamond
B
B
Hahn
B H
BH
D000293:Adolescent; D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D018949:Antigens, CD1 / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008211:Lymphocyte Cooperation; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D018949:Antigens, CD1; D007074:Immunoglobulin G; D020033:Protein Isoforms; D015847:Interleukin-4