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* Division of Cell Signaling Regulation, Genome and Drug Research Center, and
Division of Immunobiology,
Division of Molecular Biology, and
Flow Cytometry Facility, Research Institute for Biological Sciences, and
¶ Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan; and
|| Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan
Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression.
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 a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
2 M.W. and Y.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Ryo Abe, Research Institute for Biological Sciences, Tokyo University of Sciences, 2669 Yamazaki, Noda, Chiba 278-0022, Japan. E-mail address: rabe{at}rs.noda.tus.ac.jp
4 Abbreviations used in this paper: ICOSL, ICOS ligand; GC, germinal center; GVHR, graft-vs-host reaction; CSR, class switch recombination; Tg, transgenic; KO, knockout; NP, 4-hydroxy-3-nitrophenyl; BAFF, B cell activation factor of the TNF family; ActD, actinomycin D; CHX, cycloheximide; TD, T dependent; WT, wild type; KLH, keyhole limpet hemocyanin; DIG, digoxigenin; Treg, regulatory T cell; Alum, Aluminum hydroxide.
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