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Notch Ligands Expressed by Follicular Dendritic Cells Protect Germinal Center B Cells from Apoptosis

Sun-Ok Yoon^*, Xin Zhang^*, Paul Berner^*, Bianca Blom and Yong Sung Choi^1,*

^* Laboratory of Cellular Immunology, Ochsner Clinic Foundation, New Orleans, LA 70121; and Department of Cell Biology and Histology of the Academic Medical Center, University of Amsterdam, The Netherlands

The Notch signaling pathway is one of the most conserved mechanisms to regulate cell fate in many tissues during development and postnatal life. In the immune system, Notch signaling regulates T and B cell development and modulates the differentiation of T and B cells. In this study, we investigated the functional roles of Notch signaling in human B cell differentiation within the germinal center (GC). Notch ligands, Delta-like 1 (Dll1) and Jagged 1 (Jg1), are expressed by follicular dendritic cells (FDC) but not by B cells in the GC, while GC-B cells express the Notch receptors, Notch1 and Notch2. The blockade of Notch signaling pathways using a -secretase inhibitor, DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester), reduces the survival of GC-B cells in the presence of FDC/HK cells. Jg1 has a dominant effect on GC-B cell survival mediated by Notch signaling. Furthermore, Notch cooperates with another anti-apoptotic factor, BAFF/Blys produced by FDC to support GC-B cell growth. Taken together, our data shows the important role of Notch signaling provided by FDC in the survival of GC-B cells in vitro.

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. Yong Sung Choi, Laboratory of Cellular Immunology, 1514 Jefferson Highway, Ochsner Clinic Foundation, New Orleans, LA 70121. E-mail address: ychoi{at}ochsner.org

² Abbreviations used in this paper: ICN, intracellular portion of Notch; GC, germinal center; FDC, follicular dendritic cell; PC, plasma cell; FDC-SM, FDC signaling molecule; Dll1, Delta-like 1; Jg1, Jagged 1; Jg2, Jagged 2; GSI, -secretase inhibitor; DAPT, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester; PI, propidium iodide.

³ The online version of this article contains supplemental material.