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.

杂种Th1 / Tfh细胞（IFN-γ ⁺ IL-21 ⁺ CXCR5 ⁺）占主导地位，以应对多种持续性感染。在chabaudi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细胞影响最终清除，表明该杂种种群的进化驱动力。我们发现，CD4固有的Bcl6，Blimp-1和STAT3协同调节Th1主调节剂T-bet的表达，从而支持CD4 T细胞的可塑性。Bcl6和Blimp-1调节CXCR5水平，T-bet，IL-27Rα和STAT3调节杂交Th1 / Tfh细胞中的细胞因子。STAT3基因敲除（KO）T细胞感染的小鼠产生的抗体较少，而Th1类IFN-γ却更多⁺ IL-21 ^- CXCR5^低位效应细胞和记忆细胞，受到保护免于再次感染。相反，T-bet KO小鼠经再次感染后Th1-bias减少，继发性寄生虫病延长。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的调节，记忆T细胞的细胞因子谱可以被修饰以增强次级反应的有效性。