HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tuettenberg, A. Articles by Jonuleit, H. Search for Related Content PubMed PubMed Citation Articles by Tuettenberg, A. Articles by Jonuleit, H.

The Role of ICOS in Directing T Cell Responses: ICOS-Dependent Induction of T Cell Anergy by Tolerogenic Dendritic Cells¹

Andrea Tuettenberg^2,*, Eva Huter^2,4,*, Mario Hubo^2,*, Julia Horn, Jürgen Knop^*, Bodo Grimbacher^5,, Richard A. Kroczek, Sabine Stoll^3,6,* and Helmut Jonuleit^3,6,*

^* Department of Dermatology, University of Mainz, Mainz, Germany; Department of Rheumatology and Clinical Immunology, University of Freiburg, Freiburg, Germany; and Molecular Immunology, Robert Koch Institute, Berlin, Germany

Tolerogenic dendritic cells (DC) play an important role in maintaining peripheral T cell tolerance in steady-state conditions through induction of anergic, IL-10-producing T cells with suppressive properties. ICOS, an activation-induced member of the CD28 family on T cells, is involved in the induction of IL-10, which itself could contribute to induction of anergy and development of suppressive T cells. Therefore, we analyzed the functional role of ICOS in the differentiation process of human CD4⁺ T cells upon their interaction with tolerogenic DC. We compared the functional properties of CD4⁺ T cells from healthy volunteers and ICOS-deficient patients after stimulation with tolerogenic DC. We report that induction of T cell anergy and suppressive capacity is completely blocked after knockdown of ICOS expression in T cells as well as after blocking of ICOS-ICOS ligand interaction in DC/T cell cocultures. Moreover, CD4⁺ T cells from ICOS-deficient patients were completely resistant to anergy induction and differentiation into suppressive T cells even after supplementation of IL-10. Furthermore, ICOS/ICOS ligand interaction stabilizes IL-10R expression on T cells and thus renders them sensitive to IL-10 effects. Taken together, these results indicate a crucial role for ICOS in the induction of peripheral tolerance maintained by tolerogenic DC mediated mostly via an IL-10-independent mechanism.

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 the Deutsche Forschungsgemeinschaft Grants SFB-548-A8, SFB-432-B11, and Transregio TR52-TPA2 (to H.J.).

² These authors contributed equally to this work.

³ Both senior authors contributed equally.

⁴ Current address: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.

⁵ Current address: Royal Free Hospital, University College London, U.K.

⁶ Address correspondence and reprint requests to Drs. Sabine Stoll and Helmut Jonuleit, Department of Dermatology, University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany. E-mail address: jonuleit{at}hautklinik.klinik.uni-mainz.de

⁷ Abbreviations used in this paper: DC, dendritic cell; CVID, common variable immunodeficiency; EAE, experimental allergic encephalomyelitis; iDC, immature DC; iTreg, induced Treg; mDC, mature DC; siRNA, small interfering RNA; Treg, regulatory T cell.