Expression and function of the adaptor protein Gads in murine B cells

Nearly all hematopoietic receptors are dependent on adaptor proteins for the activation of downstream signaling pathways. The Gads adaptor protein is expressed in many hematopoietic tissues, including bone marrow, lymph node, and spleen. Using intracellular staining, we detected Gads protein in a number cells, including B cells, T cells, NK cells, monocytes, and plasmacytoid DC, but not in macrophages, neutrophils, or monocyte-derived DC. In the B cell compartment, Gads was first expressed after immature B cells leave the bone marrow and was down-regulated after B cell antigen receptor (BCR) ligation. Female Gads(-/-) mice had increased numbers of splenic B cells, as compared to female Gads(+/+) mice, suggesting a role for Gads in B cell homeostasis. Although B cell production and turnover of splenic B cell subsets appeared normal in Gads(-/-) mice, homeostatic proliferation was significantly impaired in Gads(-/-) B cells. Whereas BCR ligation can induce apoptosis in wild-type transitional stage 1 (T1) B cells, Gads(-/-) T1 B cells were resistant to BCR-induced apoptosis. Gads(-/-) B cells also showed increased BCR-mediated calcium mobilization. We conclude that Gads may have a negative regulatory role in signaling through survival pathways, and is necessary for normal homeostatic proliferation in B cells.