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* Department of Molecular Oncology, Graduate School of Medicine,
Department of Frontier Biosciences, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan; and
Laboratory for Cytokine Signaling, Institute of Physical and Chemical Research, Research Center for Allergy and Immunology, Kanagawa, Japan
Grb2-associated binder 1 (Gab1) is a member of the Gab/daughter of
sevenless family of adapter molecules involved in the signal
transduction pathways of a variety of growth factors, cytokines, and Ag
receptors. To know the role for Gab1 in hematopoiesis and immune
responses in vivo, we analyzed radiation chimeras reconstituted with
fetal liver (FL) cells of Gab1-/- mice, because
Gab1-/- mice are lethal to embryos. Transfer of
Gab1-/- FL cells of 14.5 days post-coitum rescued
lethally irradiated mice, indicating that Gab1 is not essential for
hematopoiesis. Although mature T and B cell subsets developed normally
in the peripheral lymphoid organs, reduction of pre-B cells and
increase of myeloid cells in the Gab1-/- FL chimeras
suggested the regulatory roles for Gab1 in hematopoiesis. The chimera
showed augmented IgM and IgG1 production to thymus-independent (TI)-2
Ag, although they showed normal responses for thymus-dependent and TI-1
Ags, indicating its negative role specific to TI-2 response.
Gab1-/- splenic B cells stimulated with
anti-
-dextran plus IL-4 plus IL-5 showed augmented IgM and IgG1
production in vitro that was corrected by the retrovirus-mediated
transfection of the wild-type Gab1 gene, clearly demonstrating
the cell-autonomous, negative role of Gab1. Furthermore, we showed that
the negative role of Gab1 required its Src homology 2-containing
tyrosine phosphatase-2 binding sites. Cell fractionation analysis
revealed that nonfollicular B cells were responsible for the augmented
Ab production in vitro. Consistent with these results, the Gab1 gene
was expressed in marginal zone B cells but not follicular B cells.
These results indicated that Gab1 is a unique negative regulator
specific for TI-2 responses.
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