PP6 controls T cell development and homeostasis by negatively regulating distal TCR signaling.
T cell development and homeostasis are both regulated by TCR signals. Protein phosphorylation and dephosphorylation, which are catalyzed by protein kinases and phosphatases, respectively, serve as important switches controlling multiple downstream pathways triggered by TCR recognition of Ags. It has been well documented that protein tyrosine phosphatases are involved in negative regulation of proximal TCR signaling. However, how TCR signals are terminated or attenuated in the distal TCR signaling pathways is largely unknown. We investigated the function of Ser/Thr protein phosphatase (PP) 6 in TCR signaling. T cell lineage-specific ablation of PP6 in mice resulted in enhanced thymic positive and negative selection, and preferential expansion of fetal-derived, IL-17-producing Vγ6Vδ1(+) T cells. Both PP6-deficient peripheral CD4(+) helper and CD8(+) cytolytic cells could not maintain a naive state and became fast-proliferating and short-lived effector cells. PP6 deficiency led to profound hyperactivation of multiple distal TCR signaling molecules, including MAPKs, AKT, and NF-κB. Our studies demonstrate that PP6 acts as a critical negative regulator, not only controlling both αβ and γδ lineage development, but also maintaining naive T cell homeostasis by preventing their premature activation before Ag stimulation.
Duke Scholars
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Related Subject Headings
- T-Lymphocytes
- Signal Transduction
- Reverse Transcriptase Polymerase Chain Reaction
- Receptors, Antigen, T-Cell
- Real-Time Polymerase Chain Reaction
- Phosphoprotein Phosphatases
- Mice, Transgenic
- Mice, Inbred C57BL
- Mice
- Lymphocyte Activation
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- T-Lymphocytes
- Signal Transduction
- Reverse Transcriptase Polymerase Chain Reaction
- Receptors, Antigen, T-Cell
- Real-Time Polymerase Chain Reaction
- Phosphoprotein Phosphatases
- Mice, Transgenic
- Mice, Inbred C57BL
- Mice
- Lymphocyte Activation