Possible relationships among classic Th2, IL-4-producing Tfh, and Th9 cells. Depending on the cytokine milieu, naive CD4 T cells may differentiate directly into Th2, Tfh, and Th9 cells once they are activated (33, 121, 280, 281). Classic Th2 cells may become IL-4-producing Tfh cells upon receiving IL-6/IL-21 and ICOSL stimulation or IL-9-producing cells upon receiving TGF-β signaling. Whether Th9 cells or IL-4-producing Tfh cells can become classic Th2 cells is not known. The transcription factor directly responsible for IL-9 production has not been identified.