CD22 ligand-binding and signalling domains reciprocally regulate B-cell Ca2+ signalling
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1
Friedrich-Alexander University Erlangen-Nuremberg, Biology, Germany
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2
University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, Faculty of Biology, Germany
The transmembrane protein CD22 mediates the inhibition of calcium signal after BCR crosslinking. The extracellular domain of CD22 can bind to α2,6-linked sialic acids, while the cytoplasmic domain contains inhibitory motifs (ITIMs). In this study we wanted to analyse the ligand-binding and signalling domain of CD22 independently and thereby determine their functional interplay. We generated CD22-R130E knockin mice, in which CD22 is no longer able to bind sialic acids. The CD22-Y5,6F and CD22-Y2,5,6F mice with mutated CD22 ITIM-domains can´t recruit SHP-1 phosphatases to the CD22 cytoplasmic tail anymore.
In the bone marrow we found a reduction of recirculating B cells only in the CD22-ITIM knockin mice, but not in CD22-R130E knockin mice. In the spleen all mice had reduced marginal zone B cells. Only CD22-Y2,5,6F B cells showed also increased turnover in vivo and spontaneous cell death in vitro. Ca2+ measurements revealed a decreased flux after BCR stimulation in CD22-R130E B cells and higher flux in CD22-ITIM mutant B cells. The CD22-R130E mutation affected the CD22/BCR association, because less total, but more phosphorylated CD22 was co-precipitated with IgM.
These data indicate that the cis-ligand binding of CD22 is crucial for regulation of the B cell Ca2+ signalling. This control is mediated by ligand-dependent regulation of the association to the BCR. In contrast, the CD22-ITIM motifs are important for a direct inhibition of Ca2+ signalling. The loss of these inhibitory motifs changes the B cell turnover, the survival of the B cells and thereby affects the homeostasis of B cell populations.
Acknowledgements
This work was supported by the DFG (NI 549/6-2 and SFB643).
Keywords:
Siglec,
B-cell signaling,
inhibitory receptors,
CD22 ligand,
BCR association
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune receptors and signaling
Citation:
Müller
J,
Obermeier
I,
Wöhner
M,
Brandl
C,
Mrotzek
S,
Maity
P,
Reth
M and
Nitschke
L
(2013). CD22 ligand-binding and signalling domains reciprocally regulate B-cell Ca2+ signalling.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00239
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Received:
12 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Ms. Jennifer Müller, Friedrich-Alexander University Erlangen-Nuremberg, Biology, Erlangen, D-91058, Germany, jennifer.mueller@fau.de