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J Biol Chem, Vol. 275, Issue 19, 14708-14716, May 12, 2000
From the Differentiation of immature
CD4+CD8+ thymocytes to mature
CD4+ or CD8+ T cells is induced by positive
selection and appears to involve calcineurin-dependent
activation of NFAT, a family of transcription factors. NFATx is
predominantly expressed in CD4+CD8+ thymocytes,
whereas NFATp and NFATc are expressed at much lower levels in the
thymus than in mature T cells. However, how or when each NFAT member is
involved in the differentiation pathway is unclear. Using an in
vitro model system where isolated
CD4+CD8+ thymocytes can survive and
differentiate into semi-mature CD4-lineage T cells, we suggest that low
calcineurin activity sustained for approximately 20 h is required
for cell survival and differentiation. Accordingly, the DNA binding
activity of NFAT slowly increased during the stimulation of 20 h
to induce the differentiation. NFATx significantly contributed to the
early rise, but the late increase was mostly due to NFATc activation.
Meanwhile, the expression of NFATx mRNA decreased and that of NFATc
mRNA increased. The DNA-binding activity of NFATp was detectable
but low throughout the stimulation. NFATp became dominantly active
after the semi-mature T cells differentiated into mature and activated
CD4 T cells. These findings suggest that NFATx and NFATc successively
play roles in T cell development.
Successive Expression and Activation of NFAT Family Members
during Thymocyte Differentiation*
,
Integrative Projects, Mitsubishi Kasei
Institute of Life Sciences, Machida-shi, Tokyo 194-8511, Japan,
§ Department of Molecular and Developmental Biology,
Institute of Medical Sciences, The University of Tokyo, CREST,
Minato-ku, Tokyo 108-0071, Japan, and ¶ Department of Immunology,
DNAX Research Institute of Molecular and Cellular Biology,
Palo Alto, California, 94304-1104
*
This work was supported in part by grants from the Ministry
of Education, Sports, Science, and Culture of Japan, the Ministry of
Public Welfare of Japan, and the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Integrative
Projects, Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194-8511, Japan. Tel.: 81-427-24-6397; Fax: 81-427-24-6316; E-mail: iwata@libra.ls.m-kagaku.co.jp.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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