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* Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan;
Department of Medicine and Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;
Department of Immunology, Dokkyo Medical University, Tochigi, Japan;
¶ Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; and
|| Department of Biotechnology, Yonsei University, Seoul, Korea
Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4+CD45RO+FoxP3+ regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-
production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-
B ligand (RANKL), lack of IFN- response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity.
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 Address correspondence and reprint requests to Dr. Tomohiro Morio, Tokyo Medical and Dental University Graduate School of Medicine, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan. E-mail address: tmorio.ped{at}tmd.ac.jp
2 Abbreviations used in this paper: ICOS-L, ICOS ligand; IBD, inflammatory bowel disease; IP, interstitial pneumonitis; RA, rheumatoid arthritis; RE, relative expression; TCM, central memory T cell; TEM, effector memory T cell; Treg, regulatory T cell; BTLA, B and T lymphocyte attenuator; EOMES, eomesodermin; PD-1, programmed death-1; RANKL, receptor activator of NF-B ligand; RORC, retinoic acid-related orphan nuclear hormone receptor.
3 The online version of this article contains supplemental material.
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