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Defining the role of CD47 and SIRPα in murine B cell homeostasis
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). (Laboratory of Innate Immune Regulation)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B cell development is a highly organized process, which commences in the fetal liver during embryogenesis and in the bone marrow (BM) after birth. Surface IgM+ immature B cells emigrate from the BM via the blood stream to the spleen and finally differentiate into conventional mature follicular B (FoB) cells and marginal zone (MZ) B cells. Conversely, some sIgM+ immature B cells can also mature into IgD+ FoB cells in the BM.

The ubiquitously expressed cell surface glycoprotein CD47 and its receptor signal regulatory protein α (SIRPα) are members of the immunoglobulin superfamily. Both individually and upon their interaction, CD47 and SIRPα have been found to play important role in the homeostasis of T lymphocytes or CD8­ conventional dendritic cells (cDCs) in secondary lymphoid organs. However, their role in regulating B cell homeostasis has remained unknown.

The present study describes important roles of CD47 and SIRPα in B cell homeostasis. Lack of SIRPα signaling in adult SIRPα mutant (MT - cytoplasmic domain deletion) mice resulted in an impaired B cell maturation in the BM and spleen, which was also reflected in the blood. In the BM and spleen of SIRPα MT mice, reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlo follicular type-I (F-I) B cells were observed, while earlier BM B cell progenitors or splenic transitional B cells remained unaltered. In SIRPα MT mice, maturing B cells in BM and spleen were found to express higher levels of the pro-apoptotic protein BIM and contained an increased level of apoptotic cells.

In contrast to that for FoB cells, the splenic MZ B cell population was increased with age in SIRPα MT mice without showing an increased level of activation markers. Immunohistochemical analysis revealed an increased follicular localization of MZ B cells in the spleens of SIRPα MT mice. In addition, MZ macrophages and marginal metallophilic macrophages were not restricted to their normal position in SIRPα MT spleens. Interestingly, CD47-deficient (CD47-/-) mice mimicked the FoB cell phenotype observed in SIRPα MT mice and had a reduced number of  FoB cells in the BM, blood and the spleen at 5­6 months of age, but not in younger mice. Similar to SIRPα MT mice, CD47-/- mice also displayed an increased number of splenic MZ B cells. Sera form both mouse strains did not show any signs of an increased production of autoantibodies or antinuclear antigens.

BM reconstitution experiments identified a requirement for non-hematopoietic SIRPα signaling for normal B cell maturation in the BM and to maintain normal numbers and retention of MZ B cells in the splenic MZ. On the contrary, hematopoietic SIRPα signaling appeared to be important for FoB cell maturation in the spleen. Interestingly, hematopoietic SIRPα was required for normal MZ retention of MZ macrophages while normal distribution of metallophilic macrophages required non­hematopoietic SIRPα signaling. 

Collectively, these findings revealed an important role of CD47 and of SIRPα signaling in B cell homeostasis in different lymphoid organs.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2015. , 64 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1742
Keyword [en]
B cells, CD47, SIRPα, Follicular B cell, Marginal zone macrophages
National Category
Cell and Molecular Biology
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-107636ISBN: 978-91-7601-324-3 (print)OAI: oai:DiVA.org:umu-107636DiVA: diva2:848526
Public defence
2015-09-24, Sal KB3A9, KBC huset, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-02 Created: 2015-08-25 Last updated: 2015-09-01Bibliographically approved
List of papers
1. Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen
Open this publication in new window or tab >>Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen
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2015 (English)In: PLoS One, Vol. 10, no 7, e0134113Article in journal (Refereed) Published
Abstract [en]

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+IgMlofollicular 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.

Place, publisher, year, edition, pages
plos one, 2015
Keyword
B cells, Bone marrow, Follicular B cells
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-107619 (URN)10.1371/journal.pone.0134113 (DOI)000358836800105 ()
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2016-07-06Bibliographically approved
2. Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells
Open this publication in new window or tab >>Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells
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2015 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 460, no 3, 645-650 p.Article in journal (Refereed) Published
Abstract [en]

Signal regulatory protein α (SIRPα) is an immunoglobulin super family protein predominantly expressed by myeloid but not lymphoid cells, and its role in lymphocyte homeostasis and function is still to be revealed. We demonstrate that mice bearing a mutant SIRPα lacking the cytoplasmic signaling domain (SIRPα MT) had an increased amount of splenic marginal zone (MZ) B cells compared to wild-type controls. Immunohistochemical analysis revealed an increased localization of MZB cells into B cell follicular areas of the white pulp in SIRPα MT spleens. However, we found no signs of an increased MZB cell activation level in MT mice. The immune response to T-independent antigens in vivo was slightly increased in SIRPα MT mice while sorted MZB from these mice responded normally to LPS in vitro. Bone marrow reconstitution experiments demonstrated that the MZB cell phenotype of SIRPα MT mice was due to lack of SIRPα signaling in non-hematopoietic cells. In contrast, MZ retention of MZ macrophages required hematopoietic SIRPα, while normal distribution of metallophilic macrophages required non-hematopoietic SIRPα signaling. In summary, these data identified SIRPα signaling in non-hematopoietic cells to play an important role in regulating the numbers and positioning MZB cell in the spleen.

Keyword
Marginal zone B cells, Signal regulatory protein alpha, Marginal zone macrophages
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-107627 (URN)10.1016/j.bbrc.2015.03.084 (DOI)000359885300026 ()
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2017-12-04Bibliographically approved
3. The Integrin Associated Protein CD47 Modulates Murine B cell Maturation
Open this publication in new window or tab >>The Integrin Associated Protein CD47 Modulates Murine B cell Maturation
(English)Manuscript (preprint) (Other academic)
Abstract [en]

CD47 is a ubiquitously expressed transmembrane glycoprotein that can function as a ligand for the inhibitory ITIM-receptor signal-regulatory protein α (SIRPα), which is highly expressed by myeloid cells but not lymphoid cells. In secondary lymphoid organs, the interaction between CD47 and SIRPα has been shown to be important in the homeostasis of T lymphocytes and CD8- dendritic cells, but a possible role in regulating B cell homeostasis remain unidentified. In the present study, we show that CD47-/- mice displayed reduced numbers of mature B cells in the bone marrow and in blood, and a reduced fraction of follicular B cells in the spleen. On the contrary, the fraction of marginal zone B cells was increased but normally localized to the splenic MZ. This B cell phenotype was found to be associated with an increasing age. However, we were unable to detect increased levels of autoantibodies in CD47-/- mice. From this investigation, no conclusion can be made whether these effects are B cell-intrinsic or secondary to other cell abnormalities. In conclusion, CD47-/- mice manifested a fairly similar B cell phenotype as we have previously described in SIRPα mutant mice (lacking the SIRPα cytoplasmic domain) and suggest that SIRPα and its ligand CD47 are important for steady-state homeostasis of B cells. 

Keyword
CD47, Bone marrow, Marginal zone B cells, Follicular B cells
National Category
Medical and Health Sciences
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-107635 (URN)
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2015-09-01Bibliographically approved

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