Members of the Slfn protein family have been implicated in the regulation of cell growth, hematopoietic cell differentiation, and T cell development/differentiation in the thymus. Ten members of this family have been described in the mouse, and they have been divided into three subgroups based on the overall sequence homology and the size of the encoded proteins. We have identified Slfn3, a member of Subgroup II, as an overexpressed gene in CD4(+) CD25(+) T cells in the periphery. Interestingly, we demonstrate that upon activation and proliferation, Slfn3 mRNA is down-regulated in CD4(+) CD25(+) Tregs and up-regulated in CD4(+) CD25(-) Teffs. Moreover, TGF-beta inhibits the expression of Slfn3 in anti-CD3/CD28-activated CD4+ T cells, and the same conditions induce FoxP3 mRNA. Our results suggest that Slfn3 could have a role in T cell differentiation and activation.