TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

Abstract

Naturally occurring CD4⁺CD25⁺ regulatory T cells (Treg) are potent suppressors of CD4⁺ and CD8⁺ T cell responses in vitro and inhibit several organ‐specific autoimmune diseases. While most in vitro studies suggest that CD4⁺CD25⁺ Treg cells adopt a cytokine‐independent but cell contact‐dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell‐derived TGF‐β1 and effector T cell responsiveness to TGF‐β in CD4⁺CD25⁺ T cell‐mediated suppression of inflammatory bowel disease (IBD). We show that CD4⁺CD25⁺ Treg cells from either TGF‐β1^+/+ or neonatal TGF‐β1^–/– mice can suppress the incidence and severity of IBD as well as colonic IFN‐γ mRNA expression induced by WT CD4⁺CD25^– effector T cells. Furthermore, TGF‐β‐resistant Smad3^–/– CD4⁺CD25⁺ Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3^–/– CD4⁺CD25^– effector T cells. Finally, anti‐TGF‐β treatment exacerbates the colitogenic potential of CD4⁺CD25^– effector T cells in the absence of CD4⁺CD25⁺ Treg cells. Together, these data demonstrate that in certain situations CD4⁺CD25⁺ T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell‐derived TGF‐β1 or effector T cell/Treg cell responsiveness to TGF‐β via Smad3.