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B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Andrew C. Vendel^*, Jill Calemine-Fenaux^*, Anita Izrael-Tomasevic^*, Vandana Chauhan, David Arnott^* and Dan L. Eaton^1,*

^* Department of Protein Chemistry and Department of Immunology, Genentech, Inc., South San Francisco, CA 94080

B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. Furthermore, effector molecules downstream of BCR signaling, including the B cell linker protein, phospholipase C2, and NF-B, display decreased activation and nuclear translocation, respectively, after BTLA activation by HVEM. These results begin to provide insight into the mechanism by which BTLA negatively regulates B cell activation and indicates that BTLA is an inhibitory coreceptor of the BCR signaling pathway and attenuates B cell activation by targeting the downstream signaling molecules Syk and B cell linker protein.

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 Address correspondence and reprint requests to Dr. Dan L. Eaton, Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080. E-mail address: eaton.dan{at}gene.com

² Abbreviations used in this paper: BTLA, B and T lymphocyte attenuator; AQUA, absolute quantification; BLNK, B cell linker protein; HVEM, herpesvirus entry mediator; LIGHT, homologous to lymphotoxin, showing inducible expression, and competing with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes; PLC2, phospholipase C2; SHP, Src homology 2 domain-containing phosphatase; SRM, slected reaction monitoring; MS, mass spectrometry.

³ The online version of this article contains supplemental material.

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