Enhanced adaptive immunity in mice lacking the immunoinhibitory adaptor Hacs1

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 inc...