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CD45 Regulates TLR-Induced Proinflammatory Cytokine and IFN-β Secretion in Dendritic Cells¹

Jennifer L. Cross, Katharine Kott, Tatjana Mileti and Pauline Johnson²

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

CD45 is a leukocyte-specific protein tyrosine phosphatase and an important regulator of AgR signaling in lymphocytes. However, its function in other leukocytes is not well-understood. In this study, we examine the function of CD45 in dendritic cells (DCs). Analysis of DCs from CD45-positive and CD45-null mice revealed that CD45 is not required for the development of DCs but does influence DC maturation induced by TLR agonists. CD45 affected the phosphorylation state of Lyn, Hck, and Fyn in bone marrow-derived DCs and dysregulated LPS-induced Lyn activation. CD45 affected TLR4-induced proinflammatory cytokine and IFN-β secretion and TLR4-activated CD45-null DCs had a reduced ability to activate NK and Th1 cells to produce IFN-. Interestingly, the effect of CD45 on TLR-induced cytokine secretion depended on the TLR activated. Analysis of CD45-negative DCs indicated a negative effect of CD45 on TLR2 and 9, MyD88-dependent cytokine production, and a positive effect on TLR3 and 4, MyD88-independent IFN-β secretion. This indicates a new role for CD45 in regulating TLR-induced responses in DCs and implicates CD45 in a wider regulatory role in innate and adaptive immunity.

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 a grant from the Canadian Institutes of Health Research (to P.J.).

² Address correspondence and reprint requests to Dr. Pauline Johnson, Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Life Sciences Institute, Vancouver, British Columbia V6T 1Z3, Canada. E-mail address: pauline{at}interchange.ubc.ca

³ Abbreviations used in this paper: DC, dendritic cell; TRIF, Toll/IL-1R-containing adaptor inducing IFN-β; BMDC, bone marrow-derived DC; MHCII, MHC class II; Wt, wild type.