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Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
IL-4 plays a critical role in the differentiation of
TCR-stimulated naive CD4 T cells to the Th2 phenotype. In response to
IL-4, the IL-4R activates a set of phosphotyrosine binding
domain-containing proteins, including insulin receptor substrate 1/2,
Shc, and IL-4R interacting protein, as well as Stat6. Stat6 has been
shown to be required for Th2 differentiation. To determine the roles of
the phosphotyrosine binding adaptors in Th2 differentiation, we
prepared a retrovirus containing a mutant of the human (h)IL-4R
-chain, Y497F, which is unable to recruit these adaptors. The mutant
hIL-4R, as well as the wild-type (WT) hIL-4R, was introduced into
naive CD4 T cells. Upon hIL-4 stimulation, Y497F worked as well as the
WT hIL-4R in driving Th2 differentiation, as measured by Gata3
up-regulation and IL-4 production. Furthermore, IL-4-driven cell
expansion was also normal in the cells infected with Y497F, although
cells infected with Y497F were not capable of phosphorylating insulin
receptor substrate 2. These results suggest that the signal pathway
mediated by Y497 is dispensable for both IL-4-driven Th2
differentiation and cell expansion. Both WT and Y497F hIL-4R lose
the ability to drive Th2 differentiation and cell expansion in
Stat6-knockout CD4 T cells. A constitutively activated form of Stat6
introduced into CD4 T cells resulted in both Th2 differentiation and
enhanced cell expansion. Thus, activated Stat6 is necessary and
sufficient to mediate both IL-4-driven Th2 differentiation and cell
expansion in CD4 T cells.
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