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

Abstract

Tgf-β1^-/- mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-β1^-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-β1^-/- 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-β1^-/- mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), α_Eβ7 integrin, and Foxp3. Adoptive transfer of Tgf-β1^-/- splenocytes to Tgf-β1^+/+/Rag2^-/- mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-β1^-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-β1^-/- CD4⁺CD25⁺ T cells from donor splenocytes. Cotransfer of Tgf- β1^-/- CD4⁺CD25⁺ T cells clearly attenuated disease in Rag2^-/- recipients of CD25⁺-depleted Tgf-β1^-/- spleen and lymph node cells, but suppression was incomplete when compared with Tgf-β1^+/+ CD4⁺CD25⁺ T cells. These data demonstrate that CD4⁺CD25⁺ regulatory T cells develop in complete absence of endogenous transforming growth factor-β1 (TGF-β1) expression and that autocrine TGF-β1 expression is not essential for these cells to suppress inflammation in vivo. (Blood. 2004;103:4594-4601)