Intravenous injection of a D1 protein of the Smith proteins postpones murine lupus and induces type 1 regulatory T cells

T cells that recognize nucleoproteins are required for the production of anti-dsDNA Abs involved in lupus development. SmD1 83-119 (a D1 protein of the Smith (Sm) proteins, part of small nuclear ribonucleoprotein) was recently shown to provide T cell help to anti-dsDNA Abs in the NZB/NZW model of lupus. Using this model in the present study, we showed that high dose tolerance to SmD1 (600-1000 microg i.v. of SmD1(83-119) peptide/mo) delays the production of autoantibodies, postpones the onset of lupus nephritis as confirmed by histology, and prolongs survival. Tolerance to SmD1 83-119 was adoptively transferred by CD90+ T cells, which also reduce T cell help for autoreactive B cells in vitro. One week after SmD1 83-119 tolerance induction in prenephritic mice, we detected cytokine changes in cultures of CD90+ T and B220+ B cells with decreased IFN-gamma and IL-4 expression and an increase in TGFbeta. Increased frequencies of regulatory IFN-gamma+ and IL10+ CD4+ T cells were later detected. Such regulatory IL-10+/IFN-gamma+ type 1 regulatory T cells prevented autoantibody generation and anti-CD3-induced proliferation of naive T cells. In conclusion, these results indicate that SmD1 83-119 peptide may play a dominant role in the activation of helper and regulatory T cells that influence autoantibody generation and murine lupus.