T cell receptor V beta genes expressed by IgG anti-DNA autoantibody-inducing T cells in lupus nephritis: forbidden receptors and double-negative T cells.
In the (SWR x NZB)F1 (SNF1) model of lupus nephritis, pathogenic variety of IgG anti-DNA autoantibodies are induced by certain T helper (Th) cells that are either CD4+ or CD4-CD8- (double negative; DN) in phenotype. From the spleens of eight SNF1 mice with lupus nephritis, 149 T cell lines were derived and out of these only 25 lines (approximately 17%) were capable of augmenting the production of pathogenic anti-DNA autoantibodies. Herein, we analyzed the T cell receptor (TcR) V beta genes used by 16 such pathogenic autoantibody-inducing Th cell lines. Twelve of the Th lines were CD4+ and among these five lines expressed V beta 8 (8.2 or 8.3). The V beta 8 gene family is contributed by the NZB parent to the SNF1 mice, since it is absent in the SWR parental strain. Three other CD4+ Th lines expressed V beta 4, another was V beta 2+ and one line with poor autoantibody-inducing capability expressed V beta 1. Four autoantibody-inducing Th lines from the SNF1 mice had a DN phenotype and these lines were also autoreactive, proliferating in response to syngeneic spleen cells. Among these DN Th lines, two expressed V beta 6 and one expressed V beta 8.1 TcR. Both of these are forbidden TcR directed against Mls-1a (Mlsa) autoantigens expressed by the SNF1 mice and such autoreactive T cells should have been deleted during thymic ontogeny. Thus, the DN Th cells of non-lpr SNF1 mice are different from the DN cells or MRL-lpr which lack helper activity and do not express forbidden TcR. The spleens of 6 out of 19 nephritic SNF1 animals tested also showed an expansion of forbidden autoreactive TcR+ cells that were mainly DN. Two of these animals expressed high levels of V beta 6 (anti-Mlsa) and V beta 11 (anti-I-E) TcR+ cells, three others had high levels of V beta 11+ cells alone and one animal had an expanded population of V beta 17a+ (anti-I-E) cells. The I-E-reactive TcR again should have been eliminated in the SNF1 thymus, since they express I-E molecules contributed by the NZB parent. The SWR parents of SNF1, are I-E-; moreover, they lack the V beta 11 gene but they express V beta 17a in peripheral T cells. Whereas the NZB parents are I-E+, they lack a functional V beta 17a gene and they delete mature V beta 11+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Adams
S
S
Department of Medicine, New England Medical Center, Boston, MA 02111.
Zordan
T
T
Sainis
K
K
Datta
S
S
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D002460:Cell Line; D004195:Disease Models, Animal; D005816:Genetic Complementation Test; D007074:Immunoglobulin G / Q000096:biosynthesis; D008181:Lupus Nephritis / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta