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

doi:10.1016/j.isci.2020.101310

T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria

iScience. 2020 Jul 24;23(7):101310. doi: 10.1016/j.isci.2020.101310. Epub 2020 Jun 24.

Authors

Victor H Carpio¹, Florentin Aussenac², Lucinda Puebla-Clark², Kyle D Wilson¹, Alejandro V Villarino³, Alexander L Dent⁴, Robin Stephens⁵

Affiliations

¹ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-0435, USA.
² Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA.
³ Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Metabolic, and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1674, USA.
⁴ Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁵ 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. Electronic address: rostephe@utmb.edu.

Abstract

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^-CXCR5^lo 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.

Keywords: Immunology; Parasitology.

Abstract

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