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International Immunology Advance Access published online on August 13, 2007
International Immunology, doi:10.1093/intimm/dxm090
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4+ T cell subsets

Tadashi Onoda1,2, Mizanur Rahman1, Hidetoshi Nara1, Akemi Araki1, Koki Makabe3, Kouhei Tsumoto3, Izumi Kumagai3, Toshio Kudo4, Naoto Ishii5, Nobuyuki Tanaka5, Kazuo Sugamura5, Kiyoshi Hayasaka2 and Hironobu Asao1

1 Department of Immunology
2 Department of Pediatrics, Yamagata University Faculty of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan
3 Department of Biomolecular Engineering, Graduate School of Engineering
4 Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
5 Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan

Correspondence to: Correspondence to: H. Asao; E-mail: asao-h{at}med.id.yamagata-u.ac.jp

IL-21 regulates certain functions of T cells, B cells, NK cells and dendritic cells. Although activated CD4+ T cells produce IL-21, data identifying the specific CD4+ T cell subsets that produce IL-21 are conflicting. In a previous study, mouse IL-21 message was detected in TH2, whereas human IL-21 (hIL-21) message was found in both TH1 and follicular helper T cells. To identify the IL-21-secreting cell populations in human, we established a hybridoma cell line producing an anti-hIL-21 mAb. Intracellular hIL-21-staining experiments showed that hIL-21 was mainly expressed in activated CD4+ central memory T cells and in activated CD4+ effector memory T cells, but not in activated CD4+ naive T cells. Moreover, IL-21 was produced upon activation by some IFN-{gamma}-producing TH1-polarized cells and some IL-17-producing TH17-polarized cells, but not by IL-4-producing TH2-polarized cells. These results suggest that specific CD4+ T cell populations produce IL-21. In the functional analysis, we found that IL-21 significantly enhanced the cytokine-driven proliferation of CD4+ helper T cells synergistically with IL-7 and IL-15 without T cell activation stimuli. Taken together, IL-21 produced from CD4+ memory T cells may have a supportive role in the maintenance of CD4+ T cell subsets.

Keywords: homeostatic proliferation, TH1, TH17

Transmitting editor: M. Miyasaka

Received 3 April 2007, accepted 11 July 2007.


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