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Updated: Dec 29, 2025
Author Spotlight: Achieving High-Purity In Vitro Differentiation of Th17 Cells Using Cytokine Concentration Modulation
Published on: October 25, 2024
DGK α and ζ Activities Control TH1 and TH17 Cell Differentiation
Jialong Yang1, Hong-Xia Wang1, Jinhai Xie1
1Division of Allergy and Immunology, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
Insights
Diacylglycerol kinases (DGKs) regulate T helper cell differentiation. Differential DGKα and DGKζ levels impact TH1 and TH17 cell development, influencing autoimmune disease pathogenesis.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- CD4+ T helper (TH) cells are crucial for adaptive immunity and autoimmune disease pathogenesis.
- The precise regulation of TH cell differentiation by T cell receptor (TCR) signaling remains incompletely understood.
Purpose of the Study:
- To investigate the role of diacylglycerol kinases (DGKs) in regulating TH cell differentiation.
- To elucidate the impact of DGK dosage on TH subset development and function.
Main Methods:
- Utilized genetic deficiency models for DGKα and DGKζ in CD4+ T cells.
- Performed *in vitro* and *in vivo* analyses of TH cell differentiation.
- Assessed TH1, TH2, and TH17 cell populations and associated signaling pathways, including mTORC1/S6K1.
Main Results:
- Selective deficiency of DGKα or DGKζ impaired TH1 differentiation but not TH2 or TH17.
- Simultaneous ablation of DGKα and DGKζ promoted TH1 and TH17 differentiation *in vitro* and *in vivo*.
- This dual deficiency led to exacerbated airway inflammation and was linked to increased mTOR complex 1/S6K1 signaling in TH17 cells.
Conclusions:
- Diacylglycerol kinases (DGKs) play a dosage-dependent role in controlling TH cell differentiation.
- Dysregulation of DGKα and DGKζ contributes to aberrant TH1 and TH17 responses, potentially driving autoimmune pathology.
- Targeting DGK signaling may offer therapeutic strategies for immune-mediated inflammatory diseases.
Abstract:
CD4+ T helper (TH) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How TH differentiation is regulated by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on TH cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired TH1 differentiation without obviously affecting TH2 and TH17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted TH1 and TH17 differentiation in vitro and in vivo, leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of TH17 differentiation of DGKα and ζ double-deficient CD4+ T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling.
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