B and T lymphocyte attenuator regulates B cell receptor signaling by targeting Syk and BLNK.
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 Cgamma2, and NF-kappaB, 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.
Vendel
Andrew C
AC
Department of Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
Calemine-Fenaux
Jill
J
Izrael-Tomasevic
Anita
A
Chauhan
Vandana
V
Arnott
David
D
Eaton
Dan L
DL
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D000072377:Syk Kinase
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; C482586:BTLA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; D011971:Receptors, Immunologic; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase