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-β1 in a cell surface and/or secreted form, and blockade of such TGF-β1 by anti-TGF-β 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-β1 in suppression by CD4⁺CD25⁺ T cells, we show in this study that another TGF-β1-blocking molecule, recombinant latency-associated peptide of TGF-β1 (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-β-inducible surface integrin. In further studies, we show that while CD4⁺CD25⁺ T cells from TGF-β1-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-β1 produced by CD4⁺CD25⁺ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.