Abstract
B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlo follicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.
Highlights
B lymphocytes are generated from pluripotent and self-renewing hematopoietic stem cells in the bone marrow (BM) after birth [1]
Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of signal regulatory protein α (SIRPα) signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen
By investigating cd47-/- mice, we recently found that stromal cells express SIRPα, that its tyrosine phosphorylation is dependent on CD47 and that SIRPα is required for BM stromal cell osteoblastic differentiation and RANKL production [25]
Summary
B lymphocytes are generated from pluripotent and self-renewing hematopoietic stem cells in the bone marrow (BM) after birth [1]. BAFF can be produced by both hematopoietic cells (e.g. monocytes, macrophages, dendritic cells and neutrophils) and non-hematopoietic stromal cells, it has been shown that BAFF produced by radiation-resistant stromal cells is required for B cell homeostasis and survival [15] This function has been attributed to FDCs, recent findings have shown that BAFF produced by FRCs and not FDCs is required to maintain B cell homeostasis in secondary lymphoid organs [16]. Studies of mutant mice, lacking most of the cytoplasmic signaling domain of SIRPα, have shown that signaling through this receptor is important to maintain normal numbers of splenic dendritic cells and T cells [23,24]. Given the requirement of SIRPα signaling for normal function of stromal cells and the importance of these cells for B cell development, we here investigated B cell homeostasis in SIRPα signaling-mutant mice
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