TGF-β and IL-21 cooperatively stimulate activated CD8+ T cells to differentiate into Tc17 cells

• The combination of TGF-β plus IL-21 increases RORα, RORγt, and Batf mRNA levels.
• IL-21R is expressed on both naïve and activated CD8+ T cells.
• The combination of TGF-β plus IL-21, but not IL-6, converts Tc1 cells into Tc17 cells.

TGF-β together with IL-21 or IL-6 can drive the differentiation of naïve CD8+ T cells into IL-17-producing CD8+ T cells. These IL-17-producing CD8+ T cells are termed Tc17 cells. Tc17 cells preserve plasticity under various conditions in vitro and in vivo. IFN-γ-producing CD8+ T cells are termed Tc1 cells. However, Tc1 cells are considered relatively stable. In the present study, we show that the combination of TGF-β plus IL-21, but not IL-6, converts Tc1 cells into Tc17 cells; this conversion is associated with elevated RORα, RORγt, and Batf mRNA levels. These results indicate that Tc1 cells are skewed to the Tc17 cell phenotype under TGF-β plus IL-21-polarizing conditions. Furthermore, IL-6R is expressed on naïve, but not activated, CD8+ T cells. In contrast, IL-21R is expressed on both naïve and activated CD8+ T cells. Thus, differential expression profiles of IL-6R and IL-21R on naïve and activated CD8+ T cells may be one mechanism by which TGF-β plus IL-21, but not IL-6, can drive activated CD8+ T cells to differentiate into IL-17-producing cells. Taken together, these results provide a novel viewpoint for the plasticity of Tc1 cells.