Type 1 regulatory T cells in treatment of murine lupus

Systemic lupus erythematosus is a severe systemic autoimmune disease characterized by loss of tolerance towards a restricted panel of autoantigens. As a result, pathogenic autoantibodies against dsDNA or the Sm proteins occur. We identified the SmD1(83-119) peptide, the C-terminus of the spliceosomal protein SmD1, as a major B-cell and T-cell autoantigen in human and murine lupus [1–3]. In previous work we could show that intravenous high-dose application of SmD1(83-119) prolongs survival in NZB/W F1 mice and delays occurrence of anti-dsDNA autoantibodies [4]. Higher percentages of CD4⁺ T cells that produce IL-10 and interferon gamma were detected on restimulation with phorbol 12-myristate 13-acetate/ionomycin later on in the spleen, indicating involvement of type 1 regulatory T cell (Tr1 cell)-mediated tolerance [4]. Transfer of splenic CD90⁺ T cells from mice treated with high doses of SmD1(83-119) into untreated mice delayed the occurrence of anti-dsDNA autoantibodies in these recipients as well [4].

We now performed a SmD1(83-119) specific analysis of the CD4⁺ T cells after high-dose application of SmD1(83-119) and detected SmD1(83-119)-reactive CD4⁺IL-10⁺ Tr1 cells in the spleen and in draining lymph nodes after additional immunization with SmD1(83-119). In vitro experiments showed that Tr1-cell-mediated suppression of anti-DNA autoantibody production is dependent on the activity of IL-10 as the addition of neutralizing anti-IL-10 antibodies abrogated this effect. Furthermore, adoptive transfer of SmD1(83-119) reactive Tr1-cell-containing lymph node cells delayed the occurrence of anti-DNA autoantibodies in the recipient mice as well.

We conclude that high-dose application of SmD1(83-119) induces SmD1(83-119) specific tolerance in NZB/W F1 mice, which is mediated by SmD1(83-119)-reactive Tr1 cells. These results may open new ways for future autoantigen specific cell-based therapies in systemic lupus erythematosus.