The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity
Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong
Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong
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Research Article Immunology

The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity

Abstract

Forkhead box O transcriptional factors, especially FoxO1 and FoxO3a, play critical roles in physiologic and pathologic immune responses. However, the function of FoxO4, another main member of the FoxO family, in lymphoid cells is still poorly understood. Here, we showed that loss of FoxO4 in T cells augmented IFN-γ production of Th1 cells in vitro. Correspondingly, conditional deletion of FoxO4 in CD4+ T cells enhanced T cell–specific responses to Listeria monocytogenes infection in vivo. Genome-wide occupancy and transcriptomic analyses identified Dkk3 (encoding the Dickkopf-3 protein) as a direct transcriptional target of FoxO4. Consistent with the FoxO4-DKK3 relationship, recombinant DKK3 protein restored normal levels of IFN-γ production in FoxO4-deficient Th1 cells through the downregulation of lymphoid enhancer–binding factor 1 (Lef1) expression. Together, our data suggest a potential FoxO4/DKK3 axis in Th1 cell differentiation, providing what we believe to be an important insight and supplement for FoxO family proteins in T lymphocyte biology and revealing a promising target for the treatment of immune-related diseases.

Authors

Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong

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Figure 1

FoxO4 deficiency in CD4+ T cells has no apparent effect on T cell homeostasis.

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FoxO4 deficiency in CD4+ T cells has no apparent effect on T cell homeos...
(A) Real-time qPCR analysis of FoxO4 mRNA in B6 naive CD4+CD44loCD62LhiCD25− T cells differentiated for 72 hours in Th1-, Th2-, Th17-, iTreg-, and Tfh-polarizing conditions. Results are presented relative to the expression of Gapdh mRNA. (B) Flow cytometric analysis of CD4 and CD8 expression in WT and FoxO4-cKO thymocytes (n = 10). The numbers adjacent to the outlined areas or in the quadrants indicate the percentage of cells. (C) Percentages of CD4 SP, CD8 SP, and CD4/8 DP cells in WT and FoxO4-cKO thymocytes (n = 10). (D) Flow cytometric analysis of B220, TCRβ, CD4 (gated on TCRβ+), CD8 (gated on TCRβ+), CD44 (gated on TCRβ+CD4+ or TCRβ+CD8+), CD62L (gated on TCRβ+CD4+or TCRβ+CD8+), and Foxp3 (gated on TCRβ+CD4+) expression on splenocytes isolated from WT and FoxO4-cKO mice (n = 10). SSC, side scatter. (E) Absolute numbers of total cells, B220+ B cells, TCRβ+ T cells, CD4+ T cells, CD8+ T cells and Foxp3+ T cells in spleens from WT and FoxO4-cKO mice (n = 10). Each symbol in C and E represents an individual mouse. NS, by unpaired, 2-tailed Student’s t test (C and E). Data are representative of 3 independent experiments with similar results (mean ±SD in A, C, and E).