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 TCRhighHSAlow 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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