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TLR4 on Follicular Dendritic Cells: An Activation Pathway That Promotes Accessory Activity¹

Mohey Eldin M. El Shikh^*, Rania M. El Sayed^*, Yongzhong Wu^*, Andras K. Szakal and John G. Tew^2,*

^* Microbiology and Immunology, and Anatomy and Neurobiology and The Immunology Group, Virginia Commonwealth University, Richmond, VA 23298

Microbial molecular patterns engage TLRs and activate dendritic cells and other accessory cells. Follicular dendritic cells (FDCs) exist in resting and activated states, but are activated in germinal centers, where they provide accessory function. We reasoned that FDCs might express TLRs and that engagement might activate FDCs by up-regulating molecules important for accessory activity. To test this hypothesis, TLR4 expression on FDCs was studied in situ with immunohistochemistry, followed by flow cytometry and RT-PCR analysis. TLR4 was expressed on FDC reticula in situ, and flow cytometry indicated that TLR4 was expressed on surface membranes and TLR4 message was readily apparent in FDCs by RT-PCR. Injecting mice or treating purified FDCs with LPS up-regulated molecules important for accessory activity including, FDC-FcRIIB, FDC-ICAM-1, and FDC-VCAM-1. Treatment of purified FDCs with LPS also induced intracellular phospho-IB-, indicating NF-B activation, and that correlated with increased FcRIIB, ICAM-1, and VCAM-1. FDCs in C3H/HeJ mice were not activated with LPS even when mice were reconstituted with C3H/HeN leukocytes, suggesting that engagement of FDC-TLR4 is necessary for activation. Moreover, activated FDCs exhibited increased accessory activity in anti-OVA recall responses in vitro, and the FDC number could be reduced 4-fold if they were activated. In short, we report expression of TLR4 on FDCs for the first time and that engagement of FDC-TLR4 activated NF-B, up-regulated expression of molecules important in FDC accessory function, including FcRIIB, ICAM-1, and VCAM-1, as well as FDC accessory activity in promoting recall IgG responses.

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 National Institutes of Health Grant AI-17142.

² Address correspondence and reprint requests to Dr. John G. Tew, Virginia Commonwealth University, Department of Microbiology and Immunology, P.O. Box 980678, Richmond, VA 23298-0678. E-mail address: tew{at}vcu.edu

³ Abbreviations used in this paper: PRR, pattern recognition receptor; DC, dendritic cell; FDC, follicular DC; GC, germinal center; IC, immune complex; LN, lymph node; MFI, mean fluorescent intensity; PAMP, pathogen-associated molecular pattern.

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