Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection

Masahiro Ogawa; Tadashi Okamura; Shuhei Ishikura; Keiko Doi; Hiroshi Matsuzaki; Yoko Tanaka; Takeharu Ota; Kunihiro Hayakawa; Harumi Suzuki; Toshiyuki Tsunoda; Takehiko Sasazuki; Senji Shirasawa

doi:10.1371/journal.pone.0076254

Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection

PLoS One. 2013 Oct 3;8(10):e76254. doi: 10.1371/journal.pone.0076254. eCollection 2013.

Authors

Masahiro Ogawa¹, Tadashi Okamura, Shuhei Ishikura, Keiko Doi, Hiroshi Matsuzaki, Yoko Tanaka, Takeharu Ota, Kunihiro Hayakawa, Harumi Suzuki, Toshiyuki Tsunoda, Takehiko Sasazuki, Senji Shirasawa

Affiliation

¹ Department of Cell Biology, Faculty of Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan ; Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Jonan-ku, Fukuoka, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD3 Complex / metabolism*
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / cytology
CD8-Positive T-Lymphocytes / metabolism
Cell Differentiation / immunology
Clonal Selection, Antigen-Mediated / genetics*
Clonal Selection, Antigen-Mediated / immunology*
Early Growth Response Transcription Factors / genetics
Early Growth Response Transcription Factors / metabolism*
Extracellular Signal-Regulated MAP Kinases / metabolism*
Gene Expression Regulation
Immunophenotyping
Male
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Phenotype
Phosphorylation
Receptors, Antigen, T-Cell / metabolism
Thymocytes / cytology
Thymocytes / metabolism
Transcription Factors / deficiency*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

CD3 Complex
CD3 antigen, zeta chain
Early Growth Response Transcription Factors
Receptors, Antigen, T-Cell
Transcription Factors
ZFAT protein, mouse
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3

Grants and funding

This work was supported in part by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of the Science and a Grant-in-Aid for the FCAM from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.