T cell receptor alpha/beta expressing double-negative (CD4-/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis.
It is generally accepted that human Th cells express the surface glycoproteins CD4 and alpha/beta-chain heterodimer of the TCR whereas cytotoxic/suppressor cells are usually CD8+ and alpha/beta TCR+. Another minor set of T cells found in the periphery are CD4-/CD8- (double negative) and express the gamma/delta TCR; these cells can manifest MHC-restricted or nonrestricted cytotoxicity but no helper function. Herein we describe the existence of an unusual Th population in the peripheral blood of humans that are CD4-/CD8- and alpha/beta TCR+. These double-negative Th were markedly expanded in patients with the autoimmune disease SLE and along with CD4+ Th, they induced production of the pathogenic variety of anti-DNA autoantibodies that are IgG in class and cationic in charge. The cationic anti-DNA antibodies induced by the Th were markedly restricted in spectrotype indicating that an oligoclonal population of B cells were committed to produce the pathogenic autoantibodies in active lupus. IL-2-dependent T cell lines were also derived from the patients with active lupus nephritis but the majority of those T cell lines lacked pathogenic autoantibody-inducing capability. Only 4 out of 42 T cell lines from a lupus patient could induce the production of cationic IgG class anti-DNA autoantibodies. The phenotypes of the pathogenic autoantibody-inducing Th lines were similar to the Th subsets: CD4+, alpha/beta TCR+ or CD4-/CD8-, alpha/beta TCR+. These studies suggest that production of pathogenic autoantibodies in human lupus is mediated by mechanisms that are distinct from the generalized, nonspecific polyclonal B cell hyperactivity that leads to excessive production of natural autoantibodies.
Shivakumar
S
S
Department of Medicine, New England Medical Center, Boston, MA 02111.
Tsokos
G C
GC
Datta
S K
SK
D000328:Adult; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D016827:CD8 Antigens; D002412:Cations; D002460:Cell Line; D004247:DNA / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008181:Lupus Nephritis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification* / Q000276:immunology / Q000378:metabolism
D000974:Antibodies, Antinuclear; D000945:Antigens, Differentiation, T-Lymphocyte; D016827:CD8 Antigens; D002412:Cations; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D004247:DNA