Ontogenic timing, T cell receptor signal strength, and Notch signaling direct γδ T cell functional differentiation in vivo

gamma delta T cells form an integral arm of the immune system and are critical during protective and destructive immunity. However, how gamma delta T cells are functionally programmed in vivo remains unclear. Here, we employ RBPJ-inducible and KN6-transgenic mice to assess the roles of ontogenic timing, T cell receptor (TCR) signal strength, and Notch signaling. We find skewing of V gamma 1(+) cells toward the PLZF(+)Lin28b(+) lineage at the fetal stage. Generation of interleukin-17 (IL-17)-producing gd T cells is favored during, although not exclusive to, the fetal stage. Surprisingly, Notch signaling is dispensable for peripheral gamma delta T cell IL-17 production. Strong TCR signals, together with Notch, promote IL-4 differentiation. Conversely, less strong TCR signals promote Notch-independent IL-17 differentiation. Single-cell transcriptomic analysis reveals differential programming instilled by TCR signal strength and Notch for specific subsets. Thus, our results precisely define the roles of ontogenic timing, TCR signal strength, and Notch signaling in gamma delta T cell functional programming in vivo.

Automated summary

This study defined the roles of ontogenic timing, TCR signal strength, and Notch signaling in gamma delta T cell functional programming in vivo. It found a preference for IL-17-producing gd T cells during the fetal stage and revealed differential programming instilled by TCR signal strength and Notch for specific subsets through single-cell transcriptomic analysis.