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J Biol Chem, Vol. 275, Issue 19, 14708-14716, May 12, 2000

Successive Expression and Activation of NFAT Family Members during Thymocyte Differentiation^*

Satoko Adachi, Yoshiharu Amasaki^§, Shoichiro Miyatake^§, Naoko Arai^¶, and Makoto Iwata

From the  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

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.

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