During viral infection, immune cells coordinate the induction of inflammatory responses that clear infection and humoral responses that promote protection. CD4⁺ T-cell differentiation sits at the center of this axis. Differentiation toward T-helper 1 (Th1) cells mediates inflammation and pathogen clearance, while T follicular helper (Tfh) cells facilitate germinal center (GC) reactions for the generation of high-affinity antibodies and immune memory. While Th1 and Tfh differentiation occurs in parallel, these CD4⁺ T-cell identities are mutually exclusive, and progression toward these ends is determined via the upregulation of T-bet and Bcl6, respectively. These lineage-defining transcription factors act in concert with multiple networks of transcriptional regulators that tip the T-bet and Bcl6 axis in CD4⁺ T-cell progenitors to either a Th1 or Tfh fate. It is now clear that these transcriptional networks are guided by cytokine cues that are not only varied between distinct viral infections but also dynamically altered throughout the duration of infection. Thus, multiple intrinsic and extrinsic factors combine to specify the fate, plasticity, and function of Th1 and Tfh cells during infection. Here, we review the current information on the mode of action of the lineage-defining transcription factors Bcl6 and T-bet and how they act individually and in complex to govern CD4⁺ T-cell ontogeny. Furthermore, we outline the multifaceted transcriptional regulatory networks that act upstream and downstream of Bcl6 and T-bet to tip the differentiation equilibrium toward either a Tfh or Th1 fate and how these are impacted by dynamic inflammatory cues.

在病毒感染期间，免疫细胞协调诱导清除感染的炎症反应和促进保护的体液反应。CD4 ⁺ T 细胞分化位于该轴的中心。向 T 辅助 1 (Th1) 细胞的分化介导炎症和病原体清除，而 T 滤泡辅助 (Tfh) 细胞促进生发中心 (GC) 反应以产生高亲和力抗体和免疫记忆。虽然 Th1 和 Tfh 分化同时发生，但这些 CD4 ⁺T 细胞身份是相互排斥的，朝着这些目标的进展分别通过 T-bet 和 Bcl6 的上调来确定。^{这些谱系定义转录因子与多个转录调节网络协同作用，这些网络使 CD4 +}中的 T-bet 和 Bcl6 轴倾斜T 细胞祖细胞对 Th1 或 Tfh 的命运。现在很清楚，这些转录网络是由细胞因子线索引导的，这些线索不仅在不同的病毒感染之间变化，而且在整个感染期间动态变化。因此，多种内在和外在因素结合起来确定感染期间 Th1 和 Tfh 细胞的命运、可塑性和功能。在这里，我们回顾了关于谱系定义转录因子 Bcl6 和 T-bet 的作用模式的当前信息，以及它们如何单独和复杂地控制 CD4 ⁺T细胞个体发育。此外，我们概述了在 Bcl6 和 T-bet 的上游和下游起作用的多方面转录调控网络，以将分化平衡向 Tfh 或 Th1 命运倾斜，以及它们如何受到动态炎症线索的影响。