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ICOS Deficiency Is Associated with a Severe Reduction of CXCR5⁺CD4 Germinal Center Th Cells¹

Lukas Bossaller^*, Jan Burger, Ruth Draeger^*, Bodo Grimbacher^*, Rolf Knoth, Alessandro Plebani, Anne Durandy^¶, Ulrich Baumann^||, Michael Schlesier^*, Andrew A. Welcher^#, Hans Hartmut Peter^* and Klaus Warnatz^2,*

^* Division of Rheumatology and Clinical Immunology, University Clinic Freiburg, Freiburg, Germany; Department of Oncology and Hematology, University Clinic Freiburg, Freiburg, Germany; Department of Neuropathology, University Clinic Freiburg, Freiburg, Germany; Department of Pediatrics and Institute for Molecular Medicine Angello Nocivelli, University of Brescia, Brescia, Italy; ^¶ Hopital Necker, Institut National de la Santé et de la Recherche Médicale Unité 429, Paris, France; ^|| Childrens’ Hospital, Medical School Hannover, Hannover, Germany; and ^# Department of Inflammation, Amgen, Thousand Oaks, CA 91320

ICOS is expressed on activated T cells and particularly on CXCR5⁺ follicular Th cells in germinal centers (GC). Its deletion leads to a profound deficiency in memory B cell formation and switched Ab response in humans. Here, we show that in ICOS-deficient patients the generation of GCs is severely disturbed, and the numbers of circulating CXCR5⁺CD45RO⁺ memory CD4 T cells are significantly reduced, indicating an essential role of ICOS in the differentiation of CXCR5⁺CD4 T cells. The GC-specific CD57⁺CXCR5⁺ subpopulation is virtually absent. In ICOS^–/– mice, the decrease of circulating CXCR5⁺CD4 T cells reflects the reduction of CXCR5⁺ follicular Th cells in lymph nodes and spleen. Therefore, in concurrence with the absence of CXCR5⁺ T cells in the blood of CD40L-deficient patients, these data support the hypothesis that circulating CD57⁺CXCR5⁺ T cells are GC derived and thus may serve as a surrogate marker for the presence of functional GCs in humans.

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 sponsored by Deutsche Forschungsgemeinschaft Grants SFB620 TP C1 (to K.W. and H.H.P.), TP C2, and Deutsche Forschungsgemeinschaft Grant GR1617/3 (both to B.G.), Grant 2004.124.1 by the Wilhelm Sander Stiftung (to K.W.), and European Grants EU-IMPAD-QLG1-CT-200101536 and 239/99 (to B.G.).

² Address correspondence and reprint requests to Dr. Klaus Warnatz, Division of Rheumatology and Clinical Immunology, University Hospital Freiburg, Hugstetterstrasse 55, D-79106 Freiburg, Germany. E-mail address: klaus.warnatz{at}uniklinik-freiburg.de

³ Abbreviations used in this paper: GC, germinal center; T_FH cells, follicular Th cells; HEL, hen egg lysozyme; MIF, mean intensity of fluorescence; wt, wild type.

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