Carpio Victor H, Aussenac Florentin, Puebla-Clark Lucinda, Wilson Kyle D, Villarino Alejandro V, Dent Alexander L, Stephens Robin
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.
iScience. 2020 Jul 24;23(7):101310. doi: 10.1016/j.isci.2020.101310. Epub 2020 Jun 24.
Hybrid Th1/Tfh cells (IFN-γIL-21CXCR5) predominate in response to several persistent infections. In Plasmodium chabaudi infection, IFN-γ T cells control parasitemia, whereas antibody and IL-21Bcl6 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-γIL-21CXCR5 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.
混合性Th1/Tfh细胞（IFN-γ⁺IL-21⁺CXCR5⁺）在应对多种持续性感染时占主导地位。在查巴迪疟原虫感染中，IFN-γ⁺ T细胞控制寄生虫血症，而抗体和IL-21⁺Bcl6⁺ T细胞实现最终清除，这表明混合细胞群体存在进化驱动因素。我们发现，CD4细胞内源性Bcl6、Blimp-1和STAT3协同调节Th1主调节因子T-bet的表达，支持CD4 T细胞的可塑性。Bcl6和Blimp-1调节CXCR5水平，T-bet、IL-27Rα和STAT3调节混合性Th1/Tfh细胞中的细胞因子。感染了STAT3基因敲除（KO）T细胞的小鼠产生的抗体减少，Th1样IFN-γ⁺IL-21⁺CXCR5⁺效应细胞和记忆细胞增多，并受到再次感染的保护。相反，T-bet基因敲除小鼠在再次感染时Th1偏向性降低，继发性寄生虫血症持续时间延长。因此，在这种持续性感染中，CD4 T细胞群体表型的每个特征都受到独特调节，记忆T细胞的细胞因子谱可以被改变以增强二次反应的有效性。
