In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation.

The expression of interleukin-4 (IL-4) is viewed as the hallmark of a Th2 lymphocyte, whereas the subsequent action of IL-4 and IL-13, mediated through the STAT6 signaling pathway, is seen as a prerequisite for the full development of Th2 immune responses to parasites and allergens. G4 mice, whose IL-4 gene locus contains the fluorescent reporter eGFP, were used to quantify the number of Th2 cells that develop during Nippostrongylus brasiliensis- or allergen-induced immune responses under conditions where IL-4 or STAT6 was absent. Here, we show that deletion of IL-4 or STAT6 had little impact on the number or timing of appearance of IL-4-producing Th2 cells. These data indicate that in vivo differentiation of naïve CD4 T cells to Th2 status often occurs independently of IL-4 and STAT6 and that recently described pathways of Th2 cell differentiation may explain how allergens and parasites selectively induce Th2-mediated immunity.