The protein tyrosine phosphatase PTP1B is a negative regulator of CD40 and BAFF-R signaling and controls B cell autoimmunity

• DOI: 10.1084/jem.20131196
• Publication Date: 2014-03-04T05:19:49Z
• Authors: David Medgyesi; Elias Hobeika; Robert Biesen; Florian Kollert; Adriano Taddeo; Reinhard E. Voll; Falk Hiepe; Michael Reth
• Keywords: Adult; Aged, 80 and over; Male; B-Lymphocytes; 0303 health sciences; Blotting, Western; Autoimmunity; Enzyme-Linked Immunosorbent Assay; Middle Aged; Flow Cytometry; Immunohistochemistry; Article; 3. Good health; Arthritis, Rheumatoid; Mice; 03 medical and health sciences; Antirheumatic Agents; Animals; Humans; Female; CD40 Antigens; Aged; B-Cell Activation Factor Receptor; Cell Proliferation

Tyrosine phosphorylation of signaling molecules that mediate B cell activation in response to various stimuli is tightly regulated by protein tyrosine phosphatases (PTPs). PTP1B is a ubiquitously expressed tyrosine phosphatase with well-characterized functions in metabolic signaling pathways. We show here that PTP1B negatively regulates CD40, B cell activating factor receptor (BAFF-R), and TLR4 signaling in B cells. Specifically, PTP1B counteracts p38 mitogen-activated protein kinase (MAPK) activation by directly dephosphorylating Tyr182 of this kinase. Mice with a B cell–specific PTP1B deficiency show increased T cell–dependent immune responses and elevated total serum IgG. Furthermore, aged animals develop systemic autoimmunity with elevated serum anti-dsDNA, spontaneous germinal centers in the spleen, and deposition of IgG immune complexes and C3 in the kidney. In a clinical setting, we observed that B cells of rheumatoid arthritis patients have significantly reduced PTP1B expression. Our data suggest that PTP1B plays an important role in the control of B cell activation and the maintenance of immunological tolerance.