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Cutting Edge: Lipopolysaccharide Induces IL-10-Producing Regulatory CD4⁺ T Cells That Suppress the CD8⁺ T Cell Response

Joke M. M. den Haan^*, Georg Kraal^* and Michael J. Bevan

^* Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands; and Department of Immunology, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

TLR ligands are potent activators of dendritic cells and therefore function as adjuvants for the induction of immune responses. We analyzed the capacity of TLR ligands to enhance CD8⁺ T cell responses toward soluble protein Ag. Immunization with OVA together with LPS or poly(I:C) elicited weak CD8⁺ T cell responses in wild-type C57BL/6 mice. Surprisingly, these responses were greatly increased in mice lacking CD4⁺ T cells indicating the induction of regulatory CD4⁺ T cells. In vivo, neutralization of IL-10 completely restored CD8⁺ T cell responses in wild-type mice and OVA-specific IL-10 producing CD4⁺ T cells were detected after immunization with OVA plus LPS. Our study shows that TLR ligands not only activate the immune system but simultaneously induce Ag specific, IL-10-producing regulatory Tr1 cells that strongly suppress CD8⁺ T cell responses. In this way, excessive activation of the immune system may be prevented.

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 Supported by grants from the Netherlands Organization of Scientific Research and the Howard Hughes Medical Institute.

² Address correspondence and reprint requests to Dr. Joke M. M. den Haan, Molecular Cell Biology and Immunology, Free University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: j.denhaan{at}vumc.nl

³ Abbreviations used in this paper: DC, dendritic cell; Treg, regulatory T cell.

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