Differential Regulation of IL-4Rα Expression by Antigen versus Cytokine Stimulation Characterizes Th2 Progression In Vivo

IL-4 promotes Th2 differentiation and provides immunity to helminth infections but is also associated with allergy and asthma. This suggests that precise adjustment of IL-4 responsiveness is needed to correctly balance immune responses. The IL-4R alpha chain is an essential component of the IL-4 receptor and signals via STAT6. In this study, we show that infection with a helminth pathogen elicited broad upregulation of IL-4R alpha on bystander CD4(+) T cells in the draining lymph node, while simultaneously resulting in the loss of IL-4R alpha expression on activated Th2 cells. IL-4R alpha upregulation was restricted to the reactive lymph node, occurred within 4 d of infection, and was driven by an IL-4- and STAT6-dependent mechanism. Mice heterozygous for Stat6 exhibited reduced IL-4R alpha upregulation and a correspondingly attenuated Th2 response. Indeed, the enhanced IL-4Ra upregulation in BALB/c mice, compared with that in C57BL6 mice, predicted their stronger Th2 response. The selective downregulation of IL-4R alpha on highly activated Th cells was triggered by antigenic stimulation, was accompanied by loss of IL-7R alpha, and rendered the cells unresponsive to IL-4. Together these data reveal a tightly controlled program of changing IL-4 responsiveness that characterizes the initiation, amplification, and restriction of a Th2 response in vivo. The Journal of Immunology, 2010, 184: 615-623.