TGF-β1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice

In previous studies, we have shown that murine CD4(+)CD25(+) regulatory T cells produce high levels of TGF-beta1 in a cell surface and/or secreted form, and blockade of such TGF-beta1 by anti-TGF-beta curtails the ability of these cells to suppress CD25(-) T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-beta1 in suppression by CD4(+)CD25(+) T cells, we show in this study that another TGF-beta1-blocking molecule, recombinant latency-associated peptide of TGF-beta1 (rLAP), also reverses suppression by mouse CD4(+)CD25(+) T cells as well as their human counterparts, CD4(+)CD25(high) T cells. In addition, we show that CD25(-) T cells exposed to CD4(+)CD25(+) T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF-beta-inducible surface integrin. In further studies, we show that while CD4(+)CD25(+) T cells from TGF-beta1 -deficient mice can suppress CD25(-) T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4(+)LAP(+), but not CD4(+)LAP(-) T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-beta1 produced by CD4(+)CD25(+) T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.