Abstract
The human ZFAT gene was originally identified as a susceptibility gene for autoimmune thyroid disease. Mouse Zfat is a critical transcriptional regulator for primitive hematopoiesis and required for peripheral T cell homeostasis. However, its physiological roles in T cell development remain poorly understood. Here, we generated Zfat f/f-LckCre mice and demonstrated that T cell-specific Zfat-deletion in Zfat f/f-LckCre mice resulted in a reduction in the number of CD4+CD8+double-positive (DP) cells, CD4+single positive cells and CD8+single positive cells. Indeed, in Zfat f/f-LckCre DP cells, positive selection was severely impaired. Defects of positive selection in Zfat-deficient thymocytes were not restored in the presence of the exogenous TCR by using TCR-transgenic mice. Furthermore, Zfat-deficient DP cells showed a loss of CD3ζ phosphorylation in response to T cell antigen receptor (TCR)-stimulation concomitant with dysregulation of extracellular signal-related kinase (ERK) and early growth response protein (Egr) activities. These results demonstrate that Zfat is required for proper regulation of the TCR-proximal signalings, and is a crucial molecule for positive selection through ERK and Egr activities, thus suggesting that a full understanding of the precise molecular mechanisms of Zfat will provide deeper insight into T cell development and immune regulation.
Highlights
ZFAT was originally identified as a candidate susceptibility gene for autoimmune thyroid disease [1]
The levels of T cell antigen receptor (TCR)-stimulation-induced Egr1, Egr2 and Egr3 expression in or MHC class II-restricted TCR transgenic mice (OT-II) Zfatf/f-LckCre thymocytes were all decreased compared with those of OT-II Zfatf/f mice (Figure S3B), and together these findings suggested that the impaired phosphorylation of extracellular signal-related kinase (ERK) and early growth response protein (Egr) expression induced by TCR-stimulation was caused by molecules other than TCR itself
We found that the inductions of Egr1 and Egr2 were considerably reduced by the treatment with U0126 both in Zfatf/f and Zfatf/f-LckCre DP cells (Figure 5B), indicating that the enhancements of Egr1 and Egr2 expression by TCR-stimulation were essentially regulated by the MEK-ERK axis
Summary
ZFAT was originally identified as a candidate susceptibility gene for autoimmune thyroid disease [1]. We previously reported that Zfat-deficient (Zfat2/2) mice are embryonic lethal by embryonic day 8.5, and Zfat is a critical transcriptional regulator for primitive hematopoiesis [3], and that ZFAT is functionally involved in the regulation of apoptosis of mouse embryonic fibroblasts and MOLT24 cells [4,5]. Genetic variants of ZFAT have been reported to be associated with adult height in Japanese and Korean population [7,8] and several common diseases including hypertension and cancer [9,10]. Of great interest is that a genetic variant of ZFAT is reported to be strongly associated with interferon-b responsiveness in multiple sclerosis [11] and the severity of Hashimoto’s disease [12]. The exact functions of ZFAT during T cell development remain unknown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
