Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus.
The production of potentially pathogenic anti-DNA autoantibodies in SLE is driven by special, autoimmune T helper (Th) cells. Herein, we sequenced the T cell receptor (TCR) alpha and beta chain genes expressed by 42 autoimmune Th lines from lupus patients that were mostly CD4+ and represented the strongest inducers of such autoantibodies. These autoimmune TCRs displayed a recurrent motif of highly charged residues in their CDR3 loops that were contributed by N-nucleotide additions and also positioned there by the recombination process. Furthermore, Th lines from four of the five patients showed a marked increase in the usage of the V alpha 8 gene family. Several independent Th lines expressed identical TCR alpha and/or beta chain sequences indicating again antigenic selection. 10 of these Th lines could be tested further for antigenic specificity. 4 of the 10 pathogenic anti-DNA autoantibody-inducing Th lines responded to the non-histone chromosomal protein HMG and two responded to nucleosomal histone proteins; all presented by HLA-DR molecules. Another Th line responded to purified DNA more than nucleosomes. Thus, these autoimmune Th cells of lupus patients respond to charged epitopes in various DNA-binding nucleoproteins that are probably processed and presented by the anti-DNA B cells they selectively help.
Desai-Mehta
A
A
Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611.
Mao
C
C
Rajagopalan
S
S
Robinson
T
T
Datta
S K
SK
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D000938:Antigen-Presenting Cells / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002417:Cattle; D002460:Cell Line; D004247:DNA / Q000276:immunology*; D015870:Gene Expression; D006681:HLA-D Antigens / Q000032:analysis / Q000096:biosynthesis; D006609:High Mobility Group Proteins / Q000276:immunology; D006801:Humans; D008181:Lupus Nephritis / Q000276:immunology*; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D006681:HLA-D Antigens; D006609:High Mobility Group Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D004247:DNA