T cell receptor Vβ genes expressed by IgG anti‐DNA autoantibody‐inducing T cells in lupus nephritis: Forbidden receptors and double‐negative T cells

Abstract

In the (SWR × NZB)F₁ (SNF₁) model of lupus nephritis, pathogenic variety of IgG anti‐DNA autoantibodies are induced by certain T helper (T_h) 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 (≈ 17%) were capable of augmenting the production of pathogenic anti‐DNA autoantibodies. Herein, we analyzed the T cell receptor (TcR) V_β genes used by 16 such pathogenic autoantibody‐inducing T_h cell lines. Twelve of the T_h lines were CD4⁺ and among these five lines expressed V_β8 (8.2 or 8.3). The V_β8 gene family is contributed by the NZB parent to the SNF₁ mice, since it is absent in the SWR parental strain. Three other CD4⁺ T_h lines expressed V_β4, another was V_β2⁺ and one line with poor autoantibody‐inducing capability expressed V_β1. Four autoantibody‐inducing T_h 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 T_h lines, two expressed V_β6 and one expressed V_β8.1 TcR. Both of these are forbidden TcR directed against Mls‐1^a (Mls^a) autoantigens expressed by the SNF₁ mice and such autoreactive T cells should have been deleted during thymic ontogeny. Thus, the DN T_h 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_β6 (anti‐Mls^a) and V_β11 (anti‐I‐E) TcR⁺ cells, three others had high levels of V_β11⁺ cells alone and one animal had an expanded population of V_β17a⁺ (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_β11 gene but they express V_β17a in peripheral T cells. Whereas the NZB parents are I‐E⁺, they lack a functional V_β17a gene and they delete mature V_β11⁺ T cells. Thus, a combination of MHC class II and TcR genes inherited from the NZB and SWR parents and abnormalities in thymic deletion/selection processes may generate the autoantibody‐inducing T_h cells in the SNF₁ mice.