Research ArticleImmunology

Constrained TCRγδ-associated Syk activity engages PI3K to facilitate thymic development of IL-17A–secreting γδ T cells

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Science Signaling  20 Jul 2021:
Vol. 14, Issue 692, eabc5884
DOI: 10.1126/scisignal.abc5884

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A Goldilocks zone for γδ T cell development

T cells displaying the γδ form of the T cell receptor (TCRγδ) mediate responses to pathogens and have been implicated in autoimmune diseases. During their development in the thymus, γδ T cells can adopt an interleukin-17A–secreting fate (γδ17 cells) in response to weak TCRγδ signaling. Using an ex vivo mouse thymus culture system, Sumaria et al. found that low amounts of TCRγδ signaling stimulated similarly weak activation of the downstream kinase Syk, leading to PI3K-Akt signaling that was critical for the γδ17 fate. Increasing or decreasing the activity of this signaling axis inhibited the generation of γδ17 cells, demonstrating that the development of this subset of T cells is sensitive to TCR signal strength.


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.

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