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TLR4 Hyperresponsiveness via Cell Surface Expression of Heat Shock Protein gp96 Potentiates Suppressive Function of Regulatory T Cells¹

Jie Dai^*, Bei Liu^*, Soo Mun Ngoi^*, Shaoli Sun, Anthony T. Vella^* and Zihai Li^2,*

^* Department of Immunology, University of Connecticut School of Medicine, Farmington, CT 06030; and Dianon Systems, Stratford, CT 06615

As one of the main mediators of the endoplasmic reticulum unfolded protein response, heat shock protein gp96 is also an obligate chaperone for multiple TLRs including TLR4. We demonstrated recently that enforced cell surface expression of gp96 in a transgenic (Tg) mouse (96tm-Tg) conferred hyperresponsiveness to LPS and induced TLR4-dependent lupus-like autoimmune diseases. In this study, we investigated the function of CD4⁺CD25⁺ Foxp3⁺ regulatory T cells (T_reg) in these mice in light of the important roles of T_reg in the maintenance of peripheral tolerance against self-Ag as well as the increasing appreciation of TLR signaling on the regulation of T_reg. We found that the development of T_reg was not impaired in 96tm-Tg mice. Contrary to the prediction of dampened T_reg activity, we discovered that the suppressive functions of T_reg were increased in 96tm-Tg mice. Inactivation of T_reg during the neonatal stage of life exacerbated not only organ-specific diseases but also systemic autoimmune diseases. By crossing 96tm-Tg mice into the TLR4 null background, we demonstrated the critical roles of TLR4 in the amplification of T_reg suppressive function. These findings illustrate that gp96 plays dual roles in regulating immune responses by augmenting proinflammatory responses and inducing T_reg function, both of which are dependent on its ability to chaperone TLR4. Our study provides strong support to the notion of compensatory T_reg activation by TLR ligation to dampen inflammation and autoimmune diseases.

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 in part by the National Institutes of Health Grants CA100191 (to Z.L.) and AI 42858 (to A.T.V.). Z.L. is a clinical scholar of the Leukemia and Lymphoma Society.

² Address correspondence and reprint requests to Dr. Zihai Li, Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, Mail Code 1601, 263 Farmington Avenue, Farmington, CT 06030-1601. E-mail address: zli{at}up.uchc.edu

³ Abbreviations used in this paper: T_reg, regulatory T cell; T_eff, effector T cell; DC, dendritic cell; ANA, antinuclear Ab; GITR, glucocorticoid-induced TNFR; SEA, staphylococcal enterotoxin A; WT, wild type; Tg, transgenic.

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