Carpio, Victor H.Aussenac, FlorentinPuebla-Clark, LucindaWilson, Kyle D.Villarino, Alejandro V.Dent, Alexander L.Stephens, Robin2020-11-172020-11-172020-06-24Carpio, V. H., Aussenac, F., Puebla-Clark, L., Wilson, K. D., Villarino, A. V., Dent, A. L., & Stephens, R. (2020). T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria. IScience, 23(7), 101310. https://doi.org/10.1016/j.isci.2020.1013102589-0042https://hdl.handle.net/1805/24434Hybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+) predominate in response to several persistent infections. In Plasmodium chabaudi infection, IFN-γ+ T cells control parasitemia, whereas antibody and IL-21+Bcl6+ T cells effect final clearance, suggesting an evolutionary driver for the hybrid population. We found that CD4-intrinsic Bcl6, Blimp-1, and STAT3 coordinately regulate expression of the Th1 master regulator T-bet, supporting plasticity of CD4 T cells. Bcl6 and Blimp-1 regulate CXCR5 levels, and T-bet, IL-27Rα, and STAT3 modulate cytokines in hybrid Th1/Tfh cells. Infected mice with STAT3 knockout (KO) T cells produced less antibody and more Th1-like IFN-γ+IL-21−CXCR5lo effector and memory cells and were protected from re-infection. Conversely, T-bet KO mice had reduced Th1-bias upon re-infection and prolonged secondary parasitemia. Therefore, each feature of the CD4 T cell population phenotype is uniquely regulated in this persistent infection, and the cytokine profile of memory T cells can be modified to enhance the effectiveness of the secondary response.en-USAttribution 4.0 InternationalImmunologyparasitologyMalariaT helper cellsArticle