Integration of T Cell Receptor, Notch and Cytokine Signals Programs in Mouse γδ T Cell Effector Differentiation.

T-cells perform a wide range of tissue- and disease-specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon- (IFN) and interleukin-17 (IL-17) producing T-cells remain unknown. Here, we define the cues involved in the functional programming of T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 TCR-transduced Rag2(-/-) T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFN versus IL-17 producing T-cell subsets, with Notch and weak TCR ligands optimally enabling development of 17 cells in the presence of IL-1, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of 17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFN and IL-17 producing T-cell subsets.