SOCS3 regulates B lymphopoiesis at the immature B cell stage (86.4)

Abstract CXCL12-mediated FAK phosporylation and sustained pro-adhesive responses occur uniquely in progenitor bone marrow (BM) B cells, but not in mature peripheral B cells. Since CXCR4 receptor expression is similar at all B cell stages, we hypothesized that progenitor and mature B cells possess different mechanisms to control FAK phosphorylation. Here we demonstrate that Suppressor of Cytokine Signaling 3 (SOCS3) regulates CXCL12-induced FAK phosphorylation through the ubiquitin-proteosome pathway. CXCL12 triggers increased FAK ubiquitination in peripheral B cells and spleen B cells, but not in BM B cells. In accordance with this finding, SOCS3 expression is relatively low in progenitor BM B cells and high in peripheral blood and spleen B cells. Over-expression of SOCS3 results in decreased CXCL12-induced FAK phosphorylation and impaired adhesion to VCAM1. Next, we examined B lineage cells from MMTV-Cre SOCS3fl/flmice in which SOCS3 protein expression was reduced greater than 95%. SOCS3 deficient splenic B cells have increased and prolonged FAK phosphorylation and enhanced sustained adhesion to VCAM-1, similar to progenitor B cells. MMTV-Cre SOCS3fl/flmice have a two-fold increase in the absolute number of IgM+,IgD−, immature B cells in BM compared to wild type mice (n=8, p<0.01). IL-7 dependent pre-B cell proliferation was unaffected by SOCS3 deficiency. However, withdrawal of IL-7 induced the generation of immature B cells that survived longer in culture compared with wild type cells. Taken together, our results suggest that SOCS3 may be an important negative regulator of immature B cells by affecting their survival and pro-adhesive responses in the bone marrow microenvironment.