T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria
T Helper Plasticity Is Orchestrated by STAT3, Bcl6, and Blimp-1 Balancing Pathology and Protection in Malaria
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DOI：
10.1016/j.isci.2020.101310
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发表时间：
2020-07-24
期刊：
影响因子：
5.8
通讯作者：
Stephens, Robin
中科院分区：
文献类型：
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作者：
Carpio, Victor H.;Aussenac, Florentin;Stephens, Robin
混合Th 1/Tfh细胞（IFN-γ +IL-21（+）CXCR 5（+））在对几种持续性感染的应答中占优势。在夏氏疟原虫感染中，IFN-γ（+）T细胞控制寄生虫血症，而抗体和IL-21（+）Bcl 6（+）T细胞影响最终清除，这表明杂交群体的进化驱动力。我们发现，CD 4-内在Bcl 6，Blimp-1和STAT 3协调调节Th 1主调节因子T-bet的表达，支持CD 4 T细胞的可塑性。Bcl 6和Blimp-1调节CXCR 5水平，T-bet、IL-27 R α和STAT 3调节杂交Th 1/Tfh细胞中的细胞因子。用STAT 3敲除（KO）T细胞感染的小鼠产生更少的抗体和更多的Th 1样IFN-γ +IL-21（-）CXCR 5（lo）效应细胞和记忆细胞，并且被保护免于再感染。相反，T-bet KO小鼠在再感染和延长的继发性寄生虫血症时具有降低的Th 1偏倚。因此，CD 4 T细胞群体表型的每个特征在这种持续性感染中被独特地调节，并且记忆T细胞的细胞因子谱可以被修饰以增强次级应答的有效性。
Hybrid Th1/Tfh cells (IFN-gamma+IL-21(+)CXCR5(+)) predominate in response to several persistent infections. In Plasmodium chabaudi infection, IFN-gamma(+) 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-27R alpha, 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-gamma+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.