Tbet preserves regulatory T cell fitness during type 1 inflammation by tuning CD39 and P2X7 to mitigate toxic extracellular ATP 4509

Abstract Description Regulatory T cells (Tregs) adapt transcriptional programs similar to helper T cell (Th) lineages in response to microenvironmental cues. One example is the Th1 program, driven by IFN-γ–induced expression of Tbet. We found that during type 1 inflammation, Tregs upregulate Tbet and migrate to the interfollicular zone of secondary lymphoid organs, where they interact with dendritic cells (DCs) and recently activated Th1 cells. To investigate Tbet’s role in Tregs, we generated bone marrow chimeras using Tbetwt and Tbet−/− mice. The peripheral Treg pool was reconstituted equally by Tbetwt and Tbet−/− cells. However, following Plasmodium chabaudi infection, an IFN-γ–driven Th1 response, Tbetwt Tregs dominated due to increased apoptosis in Tbet−/− Tregs, despite comparable proliferation and activation. Using Plasmodium expressing ovalbumin and adoptive transfers, we found Tbet−/− Tregs showed mitochondrial dysfunction and heightened caspase activation. In Tbet-fate-mapping mice, Tbet expression correlated with elevated CD39 and purinergic receptor P2X7, which modulate ATP levels to prevent apoptosis. In mixed bone marrow chimeras, Tregs lacking both Tbet and P2X7 avoided apoptosis, indicating excessive ATP-P2X7 signaling causes Tbet−/− Treg apoptosis. Taken together, Tbet may preserve Treg fitness during type 1 inflammation by regulating CD39 and P2X7, maintaining a healthy Treg pool to prevent immunopathology. Funding Sources NIH DP2AI154451 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)