Murine IL-4 is able to signal via chimeric human IL-4Ralpha/mouse gamma-chain receptor.
Human IL-4Ralpha binds to mouse gammac resulting in a chimeric receptor specific for human IL-4 but not mouse IL-4, providing in principle an inducible hIL-4 system. We investigated the in vitro and in vivo characteristics of human IL-4Ralpha transgenic mice on a mouse IL-4Ralpha-deficient background (hIL-4Ralpha Tg/mIL-4Ralpha(-/-)). The integrity of lymphocyte-specific hIL-4Ralpha expression in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice was demonstrated by FACS analysis. This was confirmed in functional studies as lymphocytes responded to recombinant hIL-4 but not mIL-4 or mIL-13 in proliferation and T helper differentiation assays, demonstrating species-specificity and inducibility of the chimeric receptor in vitro. We then infected transgenic mice with Nippostrongylus brasiliensis, known to induce a strong Type 2 response in wild-type mice. As expected hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice were unable to expel N. brasiliensis worms which confirms unresponsiveness in non-lymphocytes. However they developed a Th2 cytokine and IgE response in the absence of induction with hIL-4. These results suggested that lymphocyte-specific IL-4Ralpha responsiveness was still present in vivo. Neutralization of endogenous mIL-4 resulted in inhibition of N. brasiliensis-induced Th2 cytokine and total IgE production in hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice suggesting that mIL-4 was involved. Intercrossing hIL-4Ralpha Tg/mIL-4Ralpha(-/-) mice with mIL-4(-/-)/mIL-13(-/-) mice completely abrogated Type 2 responses in N. brasiliensis infections. Together, these data demonstrate that mIL-4 triggered the hIL-4Ralpha/mgammac chimeric receptor in vivo.
Myburgh
Elmarie
E
University of Cape Town, Health Science Faculty, Institute of Infectious Disease and Molecular Medicine, Division Immunology, Cape Town, South Africa.
Horsnell
William G C
WG
Cutler
Antony J
AJ
Arendse
Berenice
B
Kubo
Masato
M
Brombacher
Frank
F
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009559:Nippostrongylus / Q000276:immunology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000276:immunology*
D053631:Interleukin Receptor Common gamma Subunit; D053662:Interleukin-4 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4