RRC ID 44674
Author Ogawa M, Okamura T, Ishikura S, Doi K, Matsuzaki H, Tanaka Y, Ota T, Hayakawa K, Suzuki H, Tsunoda T, Sasazuki T, Shirasawa S.
Title Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection.
Journal PLoS One
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.
Volume 8(10)
Pages e76254
Published 2013-1-1
DOI 10.1371/journal.pone.0076254
PII PONE-D-13-19363
PMID 24098453
PMC PMC3789737
MeSH 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
IF 2.74
Times Cited 9
Human and Animal Cells TSt-4/G-DLL1(RCB2118)