CD28 disruption exacerbates inflammation in Tgf-β1-/- mice:: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-β1

Tgf-beta1(-/-) mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-beta1(-/-) T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-beta1(-/-) mice, and we link this increase in severity to a reduction in the number of CD4(+)CD25(+) regulatory T cells. CD4(+)CD25(+) T cells develop normally in Tgf-beta1(-/-) mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), 0107 integrin, and Foxp3. Adoptive transfer of Tgf-beta1(-/-) splenocytes; to Tgf-beta1(+/+)/Rag2(-/-) mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-beta1(-/-) phenotype, and disease transfer was accelerated by the depletion of Tgf-alpha1(-/-) CD4(+)CD25(+) T cells from donor splenocytes. Cotransfer of Tgf-beta1(-/-) CD4(+)CD25(+) T cells clearly attenuated disease in Rag2(-/-) recipients of CD25(+)-depleted Tgrf-beta1(-/-) spleen and lymph node cells, but suppression was incomplete when compared with Tgf-beta1(+/+) CD4(+)CD25(+) T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-beta1 (TGF-beta1) expression and that autocrine TGF-beta1 expression is not essential for these cells to suppress inflammation in vivo. (C) 2004 by The American Society of Hematology.