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Open Access Highly Accessed Research article

Functional requirements for inhibitory signal transmission by the immunomodulatory receptor CD300a

Karen E DeBell, Venkateswara R Simhadri, John L Mariano and Francisco Borrego*

Author Affiliations

Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies HFD-123, OBP/CDER/FDA, 29 Lincoln Drive; Bldg 29B, Room 3NN18, Bethesda, MD 20892, USA

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BMC Immunology 2012, 13:23  doi:10.1186/1471-2172-13-23

Published: 26 April 2012

Abstract

Background

Activation signals can be negatively regulated by cell surface receptors bearing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). CD300a, an ITIM bearing type I transmembrane protein, is expressed on many hematopoietic cells, including subsets of lymphocytes.

Results

We have taken two approaches to further define the mechanism by which CD300a acts as an inhibitor of immune cell receptor signaling. First, we have expressed in Jurkat T cells a chimeric receptor consisting of the extracellular domains of killer-cell immunoglobulin-like receptor (KIR)2DL2 fused to the transmembrane and cytoplasmic segments of CD300a (KIR-CD300a) to explore surrogate ligand-stimulated inhibition of superantigen stimulated T cell receptor (TCR) mediated cell signaling. We found that intact CD300a ITIMs were essential for inhibition and that the tyrosine phosphorylation of these ITIMs required the src tyrosine kinase Lck. Tyrosine phosphorylation of the CD300a ITIMs created docking sites for both src homology 2 domain containing protein tyrosine phosphatase (SHP)-1 and SHP-2. Suppression of SHP-1 and SHP-2 expression in KIR-CD300a Jurkat T cells with siRNA and the use of DT40 chicken B cell lines expressing CD300a and deficient in several phosphatases revealed that SHP-1, but not SHP-2 or the src homology 2 domain containing inositol 5’ phosphatase SHIP, was utilized by CD300a for its inhibitory activity.

Conclusion

These studies provide new insights into the function of CD300a in tuning T and B cell responses.