c-Abl-deficient mice exhibit reduced numbers of peritoneal B-1 cells and defects in BCR-induced B cell activation

Abstract

A role for c-Abl in B cell development and signaling has been suggested by previous work showing that c-Abl-deficient mice have defects in bone marrow B cell development and that c-Abl-deficient B cells are hypoproliferative in response to antigen receptor stimulation. Here we show that in addition to defects in early B cell development, c-Abl-deficient mice have defects in peripheral B cell development, including reduced percentages of peritoneal B-1 cells as well as transitional and marginal zone B cells in the spleen. It has been shown that c-Abl kinase activity increases upon B cell receptor (BCR) stimulation and that one of the targets of tyrosine phosphorylation by c-Abl is CD19. However, the consequences of c-Abl activity on B cell activation and CD19 signaling remain unknown. Here, we show that c-Abl-deficient splenic B cells exhibit reduced calcium flux in response to CD19 cross-linking, consistent with a role for c-Abl in CD19-dependent signaling. Additionally, we show that c-Abl-deficient B cells are defective in their ability to be activated in response to antigen receptor engagement, suggesting a functional role for c-Abl in BCR-dependent activation signaling pathways.

Multifunctional Abl kinases in health and disease

“…Abl1-deficient mice have decreased pro-B, pre-B and peritoneal B-1 cells (Liberatore and Goff, 2009;Schwartzberg et al, 1991;Tybulewicz et al, 1991). Abl1-deficient B cells exhibit decreased proliferation in response to antibody against immunoglobulin M (IgM) and have defective B-cell-receptorinduced activation and signaling (Liberatore and Goff, 2009;Zipfel et al, 2000).…”

“…Abl1-deficient mice have decreased pro-B, pre-B and peritoneal B-1 cells (Liberatore and Goff, 2009;Schwartzberg et al, 1991;Tybulewicz et al, 1991). Abl1-deficient B cells exhibit decreased proliferation in response to antibody against immunoglobulin M (IgM) and have defective B-cell-receptorinduced activation and signaling (Liberatore and Goff, 2009;Zipfel et al, 2000). Abl kinases are activated downstream of the T cell receptor (TCR), and are required for tyrosine phosphorylation of downstream kinases (ZAP70) and adaptor proteins (LAT and Shc) that are required for maximal T cell proliferation and IL-2 production (Gu et al, 2007;Zipfel et al, 2004).…”

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

“…Of note, mice lacking SFKs and Abl family kinases have significant immunological defects, including deficits in B cell and T cell development, proliferation and function, which could alter the course of cutaneous leishmaniasis (Colucci et al, 1999;Gu et al, 2007;Kovacs et al, 2014;Liberatore and Goff, 2009;Lin et al, 1994;Silberman et al, 2008;Zipfel et al, 2004). To determine whether the immunological effects of Abl, Arg or SFK inhibition were causing the healing seen in bosutinib-treated mice, we isolated draining lymph nodes from infected DMSO and bosutinib-treated mice and profiled cytokine secretion after stimulation with parasite lysate (Soong et al, 1996).…”

“…Mice lacking SFKs have defects in macrophage recruitment (Park et al, 1999), the respiratory burst (Meng and Lowell, 1998), and B cell and T cell development and signaling (Lowell, 2011). Immunological defects in mice lacking Abl family kinases include defects in B cell and T cell development and signaling, among others; drugs affecting SFK and Abl and Arg also decrease immune cell proliferation (Gu et al, 2007;Huang et al, 2008;Liberatore and Goff, 2009;Silberman et al, 2008;Zipfel et al, 2004). All of these effects could contribute to the smaller lesions in Leishmaniainfected bosutinib-treated mice.…”

Imatinib

“…C-abl null B cells stimulated by CD19 ligation show decreased release of intracellular calcium, a marker of B cell activation. 22 C-abl also promotes B cell activation and proliferation through phosphorylation of Bruton tyrosine kinase, an important mediator of BCR's downstream signaling. Although c-abl can phosphorylate Bruton tyrosine kinase in vitro, further studies are needed to determine its physiologic importance.…”