T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria
Victor H. Carpio,
Florentin Aussenac,
Lucinda Puebla-Clark,
Kyle D. Wilson,
Alejandro V. Villarino,
Alexander L. Dent,
Robin Stephens
Affiliations
Victor H. Carpio
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
Florentin Aussenac
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
Lucinda Puebla-Clark
Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
Kyle D. Wilson
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
Alejandro V. Villarino
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Metabolic, and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1674, USA
Alexander L. Dent
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Robin Stephens
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-0435, USA; Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA; Corresponding author
Summary: Hybrid 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.
