122 : Regulation of thymocyte development by protein phosphatase 4

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• 作者：Ching-Yu Huang ; En-Wei Hsing ; Fang-Hsuean Liao ; Wan-I Hsou ; Yu-Jun Lin ; Yi-Jyun Jhou
• 刊名：Cytokine
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：63
• 期：3
• 页码：271-272
• 全文大小：54 K

文摘

TCR repertoire is regulated sequentially by three major factors: VDJ recombination, thymic selection, and peripheral homeostasis. Using mice with Lck-cre-driven conditional deletion of PP4 locus, we show that protein phosphatase 4 (PP4), the product of PP4 gene, is essential for the development of mature T cells, such that thymocyte development is completely blocked at the CD4^?CD8^? stage in the absence of PP4 protein. Further studies of PP4¡¯s functions during late thymocyte development and in mature T cells are, however, prevented by this severe developmental block. To circumvent this limitation, we introduced CD4-cre transgene into mice carrying the conditional PP4 allele (CD4cre-PP4^f/f mice). FACS analyses and mixed bone marrow chimera experiments showed that thymocyte development was retarded at multiple stages in CD4cre-PP4^f/f mice. The introduction of ¦Á¦Â TCR transgene could partially rescue thymocyte maturation, suggesting that PP4 may be important for the generation of TCR-expressing cells. Recently PP4 was shown to regulate ¦ÃH2AX during DNA repair, which shared many components with VDJ recombination. Western and immunofluorescence analyses of PP4-deficient thymocytes, however, did not reveal any defect in H2AX phosphorylation. To further study the roles of PP4 in TCR generation, we resorted to an inducible VDJ recombination system that utilized vAbl-transformed cell lines. Results from this inducible system showed that the inhibition of PP4 did not cause defects in RAG expression or DNA repair, implying that VDJ recombination per se was not tightly regulated by PP4. Instead, PP4 inhibitor significantly enhanced the induction of apoptosis in cells with on-going VDJ recombination; interestingly, ATM antagonized the effects of PP4 in this context. Our studies thus reveal a novel role of PP4 in thymocytes maturation and TCR repertoire formation, in which the survival window of thymocytes with active VDJ recombination may be critically regulated by PP4.