γδ T lymphocytes are programmed into distinct IFN-γ–producing CD27⁺ (γδ27⁺) and IL-17–producing CD27⁻ (γδ27⁻) subsets that play key roles in protective or pathogenic immune responses. Although the signature cytokines are shared with their αβ Th1 (for γδ27⁺) and Th17 (for γδ27⁻) cell counterparts, we dissect in this study similarities and differences in the transcriptional requirements of murine effector γδ27⁺, γδ27⁻CCR6⁻, and γδ27⁻CCR6⁺ γδ T cell subsets and αβ T cells. We found they share dependence on the master transcription factors T-bet and RORγt for IFN-γ and IL-17 production, respectively. However, Eomes is fully dispensable for IFN-γ production by γδ T cells. Furthermore, the Th17 cell auxiliary transcription factors RORα and BATF are not required for IL-17 production by γδ27⁻ cell subsets. We also show that γδ27⁻ (but not γδ27⁺) cells become polyfunctional upon IL-1β plus IL-23 stimulation, cosecreting IL-17A, IL-17F, IL-22, GM-CSF, and IFN-γ. Collectively, our in vitro and in vivo data firmly establish the molecular segregation between γδ27⁺ and γδ27⁻ T cell subsets and provide novel insight on the nonoverlapping transcriptional networks that control the differentiation of effector γδ versus αβ T cell subsets.

Significance: The clinically silent intracellular development of Plasmodium parasites in the host liver is a prerequisite for the onset of malaria pathology. Liver stages can be completely eliminated by sterilizing immune responses and are promising targets for urgently needed antimalarial drugs and/or vaccines. The parasite is separated from the host cell cytoplasm by a parasitophorous vacuole (PV). We show that the PV membrane protein exported protein 1 interacts specifically with host Apolipoprotein H. The characterization of this protein–protein interaction revealed an essential role for both molecular partners during intrahepatic parasite growth. Our results improve our understanding of cell-biological aspects of host–pathogen interactions and may also help to develop new strategies to control Plasmodium infections.