Abstract
Hacs1, a SH3 and SAM domain-containing adaptor protein, is up-regulated by IL-4 in activated B cells and strongly expressed in dendritic cells. To elucidate the function of Hacs1 in immune regulation, we generated Hacs1 -/- mice by deletion of the SH3 and SAM domains. Hacs1-/- mice were viable and fertile and had normal bone marrow B-cell development and normal splenic T- and B-cell populations. However, adult Hacs1-/- mice had increased peritoneal B1a cells (IgM+CD5+). On immunization with T-cell-independent antigen TNP-Ficoll, Hacs1-/- mice had increased production of anti-TNP IgM and IgG3. Purified splenic B cells from Hacs1-/- mice showed increased cell proliferation on BCR (B-cell receptor) stimulation. We further demonstrate that the Hacs1 -/- B cells had increased global tyrosine phosphorylation, including tyrosine kinases Lyn and Akt. Both T-helper type 1 (Th1) and T-helper type 2 (Th2) humoral responses were enhanced in Hacs1-/- mice. In vitro bone marrow-derived Hacs1-/- dendritic cells showed increased IL-12 production on stimulation with ovalbumin (OVA). This study suggests that Hacs1 is an immunoinhibitory adaptor that might be a useful target for immune suppression therapy.
Original language | English (US) |
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Pages (from-to) | 947-956 |
Number of pages | 10 |
Journal | FASEB Journal |
Volume | 24 |
Issue number | 3 |
DOIs | |
State | Published - Mar 1 2010 |
Keywords
- Adaptor protein
- B cells
- Dendritic cells
- Gene targeting
- Immune regulation
- SAM domain
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics