Soon after activation, CD4⁺ T cells are segregated into BCL6⁺ follicular helper (Tfh) and BCL6^– effector (Teff) T cells. Here, we explored how these subsets are maintained during chronic antigen stimulation using the mouse chronic LCMV infection model. Using single cell-transcriptomic and epigenomic analyses, we identified a population of PD-1⁺ TCF-1⁺ CD4⁺ T cells with memory-like features. TCR clonal tracing and adoptive transfer experiments demonstrated that these cells have self-renewal capacity and continue to give rise to both Teff and Tfh cells, thus functioning as progenitor cells. Conditional deletion experiments showed Bcl6-dependent development of these progenitors, which were essential for sustaining antigen-specific CD4⁺ T cell responses to chronic infection. An analogous CD4⁺ T cell population developed in draining lymph nodes in response to tumors. Our study reveals the heterogeneity and plasticity of CD4⁺ T cells during persistent antigen exposure and highlights their population dynamics through a stable, bipotent intermediate state.

激活后不久，CD4 ⁺ T 细胞被分离为 BCL6 ⁺滤泡辅助 (Tfh) 和 BCL6 ^-效应 (Teff) T 细胞。在这里，我们利用小鼠慢性 LCMV 感染模型探讨了如何在慢性抗原刺激过程中维持这些子集。^{使用单细胞转录组和表观基因组分析，我们鉴定了 PD-1 +} TCF-1 ⁺ CD4 ⁺群体T细胞具有类似记忆的功能。TCR克隆追踪和过继转移实验表明，这些细胞具有自我更新能力，并继续产生Teff和Tfh细胞，从而发挥祖细胞的作用。^{条件缺失实验表明这些祖细胞的发育依赖于 Bcl6，这对于维持抗原特异性 CD4 +} T 细胞对慢性感染的反应至关重要。类似的 CD4 ⁺ T 细胞群在引流淋巴结中形成，以应对肿瘤。^{我们的研究揭示了 CD4 +} T 细胞在持续抗原暴露期间的异质性和可塑性，并通过稳定的双能中间状态强调了它们的群体动态。