New T cell lineages in mice (a) and humans (c). When stimulated by APCs such as DCs and macrophages, and cognate peptide, naïve helper T cells differentiate into lineages determined by the cytokine milieu. TGFβ-1 is a critical factor in the differentiation of new two lineages in mice T cells. In conjunction with TCR stimulation, the combination of TGFβ-1 and IL-2 (and other γc cytokines) induces the expression of Foxp3, leading to the differentiation of naïve CD4+ T cells into anti-inflammatory Tregs (a). However, in the presence of TGFβ-1 with IL-6 or IL-21, which activates Stat3 and up-regulates RORγt, naïve CD4+ T cells develop to become pro-inflammatory Th17 cells (a). Th17 differentiation is suppressed by IFN-γ, IL-4, IL-2, IL-25, IL-27, and retinoic acid in mice (b). Both Th17 cells and Tregs are also present in humans (c). TGFβ-1, IL-1β, and IL-2 in combination with IL-6, IL-21 or IL-23 are necessary for human Th17 differentiation (c). APCs, antigen-presenting cells; iTregs, inducible Tregs