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Lack of non-hematopoietic SIRPα signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). (Laboratory of Innate Immune Regulation)
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan..
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
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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.

Place, publisher, year, edition, pages
2015. Vol. 460, no 3, 645-650 p.
Keyword [en]
Marginal zone B cells, Signal regulatory protein alpha, Marginal zone macrophages
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-107627DOI: 10.1016/j.bbrc.2015.03.084ISI: 000359885300026OAI: oai:DiVA.org:umu-107627DiVA: diva2:848502
Available from: 2015-08-25 Created: 2015-08-25 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Defining the role of CD47 and SIRPα in murine B cell homeostasis
Open this publication in new window or tab >>Defining the role of CD47 and SIRPα in murine B cell homeostasis
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
B cells, CD47, SIRPα, Follicular B cell, Marginal zone macrophages
National Category
Cell and Molecular Biology
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-107636 (URN)978-91-7601-324-3 (ISBN)
Public defence
2015-09-24, Sal KB3A9, KBC huset, Umeå Universitet, Umeå, 09:00 (English)
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Available from: 2015-09-02 Created: 2015-08-25 Last updated: 2015-09-01Bibliographically approved

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Kolan, ShrikantLejon, KristinaOldenborg, Per-Arne

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Immunology in the medical area

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