Constrained TCRγδ-associated Syk activity engages PI3K to facilitate thymic development of IL-17A–secreting γδ T cells
| Autor: | Daniel J. Pennington, Stefania Martin, Nital Sumaria |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
T-Lymphocytes T cell Syk Biology Biochemistry Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Immune system medicine Animals Molecular Biology PI3K/AKT/mTOR pathway Cell growth Interleukin-17 T-cell receptor Receptors Antigen T-Cell gamma-delta Cell Biology Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Phosphatidylinositol 3-Kinase Signal transduction CD8 030215 immunology |
| Zdroj: | Science Signaling. 14 |
| ISSN: | 1937-9145 1945-0877 |
| Popis: | Murine γδ17 cells, which are T cells that bear the γδ T cell receptor (TCRγδ) and secrete interleukin-17A (IL-17A), are generated in the thymus and are critical for various immune responses. Although strong TCRγδ signals are required for the development of interferon-γ (IFN-γ)-secreting γδ cells (γδIFN cells), the generation of γδ17 cells requires weaker TCRγδ signaling. Here, we demonstrated that constrained activation of the kinase Syk downstream of TCRγδ was required for the thymic development of γδ17 cells. Increasing or decreasing Syk activity by stimulating TCRγδ or inhibiting Syk, respectively, substantially reduced γδ17 cell numbers. This delimited Syk activity optimally engaged the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, which maintained the expression of master regulators of the IL-17 program, RORγt and c-Maf. Inhibition of PI3K not only abrogated γδ17 cell development but also augmented the development of a distinct, previously undescribed subset of γδ T cells. These CD8+Ly6a+ γδ T cells had a type-I IFN gene expression signature and expanded in response to stimulation with IFN-β. Collectively, these studies elucidate how weaker TCRγδ signaling engages distinct signaling pathways to specify the γδ17 cell fate and identifies a role for type-I IFNs in γδ T cell development. |
| Databáze: | OpenAIRE |
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