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Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
T cells differentiate from bone marrow-derived stem cells by expressing developmental stage-specific genes. We here searched arrays of genes that are highly expressed in mature CD4–CD8+ (CD8 single-positive (SP)) T cells but little in CD4+CD8+ (double-positive (DP)) cells by cDNA subtraction. Lunatic fringe (Lfng), a modulator of Notch signaling, was identified to be little expressed in DP cells and highly expressed in CD8SP T cell as well as in CD4–CD8– (double-negative (DN)) and mature CD4+CD8– (CD4SP) T cells. Thus, we examined whether such change of expression of Lfng plays a role in T cell development. We found that overexpression of Lfng in Jurkat T cells strengthened Notch signaling by reporter gene assay, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cells development due to the defective transition from CD44+CD25– stage to subsequent stage in DN cells. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggested that the physiological high expression of Lfng in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling. Shutting down the expression of Lfng in DP cells may have a physiological role in promoting DP cells differentiation toward mature SP cells.
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1 This work was supported by a grant from the Mitsubishi Foundation and Grants-In-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17047027, 17046013 (to K.Y.) and 18015035, 1806003), and Princess Takamatsu Cancer Research Fund.
2 Address correspondence and reprint requests to Dr. Koji Yasutomo, Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. E-mail address: yasutomo{at}basic.med.tokushima-u.ac.jp
3 Abbreviations used in this paper: HSC, hemopoietic stem cell; DN, double negative; DP, double positive; SP, single positive; Lfng, lunatic fringe; FL-HSC, fetal liver-derived HSC; shRNA, small hairpin RNA; dGuo, 2-deoxyguanosine.
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