Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection.
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 u...
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2013
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oai:doaj.org-article:1a91b41879c94f25b102ebd5f8a6d1d32021-11-18T08:52:38ZZfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection.1932-620310.1371/journal.pone.0076254https://doaj.org/article/1a91b41879c94f25b102ebd5f8a6d1d32013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24098453/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Masahiro OgawaTadashi OkamuraShuhei IshikuraKeiko DoiHiroshi MatsuzakiYoko TanakaTakeharu OtaKunihiro HayakawaHarumi SuzukiToshiyuki TsunodaTakehiko SasazukiSenji ShirasawaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 10, p e76254 (2013) |
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Medicine R Science Q |
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Medicine R Science Q Masahiro Ogawa Tadashi Okamura Shuhei Ishikura Keiko Doi Hiroshi Matsuzaki Yoko Tanaka Takeharu Ota Kunihiro Hayakawa Harumi Suzuki Toshiyuki Tsunoda Takehiko Sasazuki Senji Shirasawa Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. |
| description |
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. |
| format |
article |
| author |
Masahiro Ogawa Tadashi Okamura Shuhei Ishikura Keiko Doi Hiroshi Matsuzaki Yoko Tanaka Takeharu Ota Kunihiro Hayakawa Harumi Suzuki Toshiyuki Tsunoda Takehiko Sasazuki Senji Shirasawa |
| author_facet |
Masahiro Ogawa Tadashi Okamura Shuhei Ishikura Keiko Doi Hiroshi Matsuzaki Yoko Tanaka Takeharu Ota Kunihiro Hayakawa Harumi Suzuki Toshiyuki Tsunoda Takehiko Sasazuki Senji Shirasawa |
| author_sort |
Masahiro Ogawa |
| title |
Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. |
| title_short |
Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. |
| title_full |
Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. |
| title_fullStr |
Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. |
| title_full_unstemmed |
Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection. |
| title_sort |
zfat-deficiency results in a loss of cd3ζ phosphorylation with dysregulation of erk and egr activities leading to impaired positive selection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/1a91b41879c94f25b102ebd5f8a6d1d3 |
| work_keys_str_mv |
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