Differential regulation of IL-4Ralpha 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-4Ralpha 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-4Ralpha on bystander CD4+ T cells in the draining lymph node, while simultaneously resulting in the loss of IL-4Ralpha expression on activated Th2 cells. IL-4Ralpha 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-4Ralpha upregulation and a correspondingly attenuated Th2 response. Indeed, the enhanced IL-4Ralpha upregulation in BALB/c mice, compared with that in C57BL6 mice, predicted their stronger Th2 response. The selective downregulation of IL-4Ralpha on highly activated Th cells was triggered by antigenic stimulation, was accompanied by loss of IL-7Ralpha, 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.
Perona-Wright
Georgia
G
Trudeau Institute, Saranac Lake, NY 12983, USA.
Mohrs
Katja
K
Mayer
Katrin D
KD
Mohrs
Markus
M
D000818:Animals; D000941:Antigens / Q000276:immunology*; D024201:Bystander Effect; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006376:Helminths / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050800:STAT6 Transcription Factor / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
D000941:Antigens; D016207:Cytokines; D053662:Interleukin-4 Receptor alpha Subunit; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4