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 (γδ^IFN 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.

鼠 γδ ¹⁷细胞是携带 γδ T 细胞受体 (TCRγδ) 并分泌白介素 17A (IL-17A) 的 T 细胞，在胸腺中产生，对各种免疫反应至关重要。尽管分泌干扰素-γ (IFN-γ) 的 γδ 细胞（γδ ^IFN细胞）的发育需要强 TCRγδ 信号，但产生 γδ ¹⁷细胞需要较弱的 TCRγδ 信号。在这里，我们证明了 TCRγδ 下游激酶 Syk 的受限激活是 γδ ¹⁷细胞的胸腺发育所必需的。分别通过刺激 TCRγδ 或抑制 Syk 来增加或降低 Syk 活性，显着降低 γδ ¹⁷手机号码。这种限定的 Syk 活性最佳地参与了磷酸肌醇 3-激酶 (PI3K)-Akt 信号通路，该通路维持了 IL-17 程序的主要调节因子 RORγt 和 c-Maf 的表达。抑制 PI3K 不仅消除了 γδ ¹⁷细胞的发育，而且增强了独特的、以前未描述的 γδ T 细胞亚群的发育。这些 CD8 ⁺ Ly6a ⁺ γδ T 细胞具有 I 型 IFN 基因表达特征，并响应 IFN-β 刺激而扩增。总的来说，这些研究阐明了较弱的 TCRγδ 信号如何参与不同的信号通路来指定 γδ ¹⁷细胞的命运，并确定 I 型干扰素在 γδ T 细胞发育中的作用。