Activation of diverse repertoires of autoreactive T cells enhances the loss of anti-dsDNA B cell tolerance

CD4(+) helper T cells play a critical role in the production of the antinuclear autoantibodies that characterize systemic lupus erythematosus in mice and humans. A key issue is whether this help is derived from a diverse repertoire of autoreactive CD4(+)T cells or from a select number of T cells of limited specificity. We used the chronic graft-versus-host disease model to define the diversity of the CD4(+)T cell repertoire required to induce the autoantibody response. By transferring clonally restricted versus clonally diverse populations of MHC class II-reactive CD4(+)T cells, we show that the loss of B cell tolerance to nuclear antigens has two distinct components with different CD4(+) cell requirements. Activation of limited repertoires of CD4(+)T cells was sufficient for the expansion of anergized anti-double-stranded DNA B cells and production of IgM autoantibodies. Unexpectedly, we found that CD4(+)T cell diversity was necessary for CD4(+)T cell trafficking into the follicle and for the generation of isotype-switched IgG autoantibodies. Importantly, combining two limited repertoires of T cells provides sufficient CD4(+)T cell diversity to drive antinuclear Ab production. These data demonstrate that a diverse CD4(+)T cell repertoire is required to generate a sustained effector B cell response capable of mediating systemic autoimmunity.