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* Department of Molecular Genetics and
Clinical Sciences Division, University of Toronto, Toronto, Ontario, Canada
Neisseria gonorrhoeae colony opacity-associated (Opa) proteins bind to human carcinoembryonic antigen cellular adhesion molecules (CEACAM) found on host cells including T lymphocytes. Opa binding to CEACAM1 suppresses the activation of CD4+ T cells in response to a variety of stimuli. In this study, we use primary human CD4+ T cells isolated from peripheral blood to define the molecular events occurring subsequent to Opa-CEACAM1 binding. We establish that, in contrast to other cell types, T cells do not engulf N. gonorrhoeae upon CEACAM1 binding. Instead, the bacteria recruit CEACAM1 from intracellular stores and maintain it on the T cell surface. Upon TCR ligation, the co-engaged CEACAM1 becomes phosphorylated on tyrosine residues within the ITIMs apparent in the cytoplasmic domain. This allows the recruitment and subsequent activation of the src homology domain 2-containing tyrosine phosphatases SHP-1 and SHP-2 at the site of bacterial attachment, which prevents the normal tyrosine phosphorylation of the CD3
-chain and ZAP-70 kinase in response to TCR engagement. Combined, this dynamic response allows the bacteria to effectively harness the coinhibitory function of CEACAM1 to suppress the adaptive immune response at its earliest step.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Canadian Institutes for Health Research Grant MOP-15499. S.D.G. is supported by a New Investigator Award from the Canadian Institutes of Health Research and is a recipient of the Ontario Premier’s Research Excellence Award.
2 Address correspondence and reprint requests to Dr. Scott D. Gray-Owen, Department of Molecular Genetics, University of Toronto, Room 4381, Medical Sciences Building, 1 Kings College Circle, Toronto, Ontario, M5S 1A8, Canada. E-mail address: scott.gray.owen{at}utoronto.ca
3 Abbreviations used in this paper: Opa, opacity-associated protein; CEACAM, carcinoembryonic antigen-related cellular adhesion molecule; OpaCEA, CEACAM-specific Opa57; OpaHSPG, heparan sulfate proteoglycan-specific Opa50; Opa(–), no Opa; SHP, Src homology domain 2-containing phosphatase.
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