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 (T_h1) and T-helper type 2 (T_h2) 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.