Abstract
B lymphocytes are compartmentalized within lymphoid organs. The organization of these compartments depends upon signaling initiated by G-protein linked chemoattractant receptors. To address the importance of the G-proteins Gαi2 and Gαi3 in chemoattractant signaling we created mice lacking both proteins in their B lymphocytes. While bone marrow B cell development and egress is grossly intact; mucosal sites, splenic marginal zones, and lymph nodes essentially lack B cells. There is a partial block in splenic follicular B cell development and a 50-60% reduction in splenic B cells, yet normal numbers of splenic T cells. The absence of Gαi2 and Gαi3 in B cells profoundly disturbs the architecture of lymphoid organs with loss of B cell compartments in the spleen, thymus, lymph nodes, and gastrointestinal tract. This results in a severe disruption of B cell function and a hyper-IgM like syndrome. Beyond the pro-B cell stage, B cells are refractory to chemokine stimulation, and splenic B cells are poorly responsive to antigen receptor engagement. Gαi2 and Gαi3 are therefore critical for B cell chemoattractant receptor signaling and for normal B cell function. These mice provide a worst case scenario of the consequences of losing chemoattractant receptor signaling in B cells.
Highlights
Gnai1, Gnai2, and Gnai3 encode members of the “inhibitory class” of heterotrimeric G-proteins so named based on their ability to inhibit adenylyl cyclase activity [1]
The absence of Gαi2 reduced the number of B lymphocytes in the peripheral lymph nodes (LN), mesenteric LNs, and Peyer’s patches without disturbing the number of splenic B cells
To address the reduction in spleen B220+ cells in the DKO mice and to assess whether marginal zone B cell development was impaired as had been noted in the Gnai2-/- mice [7], we examined the relative distribution of the B cell populations in the spleen in the different mice
Summary
Gnai, and Gnai encode members of the “inhibitory class” of heterotrimeric G-proteins so named based on their ability to inhibit adenylyl cyclase activity [1]. Targeted loss-offunction mutations of Gnai, Gnai, and Gnai have been generated in mice revealing redundancy as well as tissue specific functions for Gαi, Gαi, and Gαi that partially depend upon the genetic background of the mice [2,3,4,5,6]. Gnai2-/mice have a reduced relative abundance of splenic marginal zone and T2 transitional B lymphocytes, reduced peritoneal B-1a B cells, and increased splenic follicular and peritoneal Β-1b B cells [7]. These phenotypes arise as a consequence of a lymphocyte intrinsic defect as Gnai2-/- bone marrow reconstituted RAG2-/- mice have a similar B cell phenotype [7].
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