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Overexpression of the Runx3 Transcription Factor Increases the Proportion of Mature Thymocytes of the CD8 Single-Positive Lineage¹

Kazuyoshi Kohu^*, Takehito Sato, Shin-ichiro Ohno, Keitaro Hayashi^*, Ryuji Uchino^*, Natsumi Abe^*, Megumi Nakazato^*, Naomi Yoshida^*, Toshiaki Kikuchi, Yoichiro Iwakura^¶, Yoshihiro Inoue, Toshio Watanabe^*, Sonoko Habu and Masanobu Satake^2,*

Departments of ^* Molecular Immunology, and Oncology and Molecular Medicine, and Animal Research Facility, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; Department of Immunology, Tokai University School of Medicine, Isehara, Japan; and ^¶ Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

The Runx family of transcription factors is thought to regulate the differentiation of thymocytes. Runx3 protein is detected mainly in the CD4^–8⁺ subset of T lymphocytes. In the thymus of Runx3-deficient mice, CD4 expression is de-repressed and CD4^–8⁺ thymocytes do not develop. This clearly implicates Runx3 in CD4 silencing, but does not necessarily prove its role in the differentiation of CD4^–8⁺ thymocytes per se. In the present study, we created transgenic mice that overexpress Runx3 and analyzed the development of thymocytes in these animals. In the Runx3-transgenic thymus, the number of CD4^–8⁺ cells was greatly increased, whereas the numbers of CD4⁺8⁺ and CD4⁺8^– cells were reduced. The CD4^–8⁺ transgenic thymocytes contained mature cells with a TCR^highHSA^low phenotype. These cells were released from the thymus and contributed to the elevated level of CD4^–8⁺ cells relative to CD4⁺8^– cells in the spleen. Runx3 overexpression also increased the number of mature CD4^–8⁺ thymocytes in mice with class II-restricted, transgenic TCR and in mice with a class I-deficient background, both of which are favorable for CD4⁺8^– lineage selection. Thus, Runx3 can drive thymocytes to select the CD4^–8⁺ lineage. This activity is likely to be due to more than a simple silencing of CD4 gene expression.

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