Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors

gamma delta T lymphocytes are programmed into distinct IFN-gamma-producing CD27(+) (gamma delta 27(+)) and IL-17-producing CD27(-) (gamma delta 27(-)) subsets that play key roles in protective or pathogenic immune responses. Although the signature cytokines are shared with their alpha beta Th1 (for gamma delta 27(+)) and Th17 (for gamma delta 27(-)) cell counterparts, we dissect in this study similarities and differences in the transcriptional requirements of murine effector gamma delta 27(+), gamma delta 27(-)CCR6(-), and gamma delta 27(-)CCR6(+) gamma delta T cell subsets and alpha beta T cells. We found they share dependence on the master transcription factors T-bet and ROR gamma t for IFN-gamma and IL-17 production, respectively. However, Eomes is fully dispensable for IFN-gamma production by gamma delta T cells. Furthermore, the Th17 cell auxiliary transcription factors ROR alpha and BATF are not required for IL-17 production by gamma delta 27(-) cell subsets. We also show that gamma delta 27(-) (but not gamma delta 27(+)) cells become polyfunctional upon IL-1 beta plus IL-23 stimulation, cosecreting IL-17A, IL-17F, IL-22, GM-CSF, and IFN-gamma. Collectively, our in vitro and in vivo data firmly establish the molecular segregation between gamma delta 27(+) and gamma delta 27(-) T cell subsets and provide novel insight on the nonoverlapping transcriptional networks that control the differentiation of effector gamma delta versus alpha beta T cell subsets.