美国埃默里大学医学院Haydn T. Kissick团队近期取得重要工作进展，他们研究提出，干细胞样CD4 T细胞的分化命运控制着对癌症的免疫。相关研究成果2024年10月23日在线发表于《自然》杂志上。

据介绍，T细胞对癌症的反应控制着疾病进展和对免疫疗法的反应。尽管对CD8 T细胞有广泛的了解，但CD4 T细胞如何参与这一过程尚不清楚。

研究人员鉴定了具有干细胞样特性的PD1⁺ TCF1⁺ CD4 T细胞群，这些细胞能够自我更新并分化为典型的CD4效应细胞。这些肿瘤特异性CD4 T细胞主要存在于肿瘤引流淋巴结（TDLN）中，受T调节（T_reg）细胞的限制，具有干细胞样命运，主要产生诱导性T_reg（iT_reg）细胞，限制效应CD8 T细胞对肿瘤的反应。

相比之下，在T_reg耗竭后，干细胞样CD4 T细胞分化为T辅助1（T_H1）细胞，并通过IFNγ的产生诱导TDLN中TCF1⁺ CD8 T细胞产生强大的效应器分化，研究人员将这种状态定义为“活性”。在转移的干细胞样CD4 T细胞中加强TBET表达足以克服既定的限制性T细胞状态。

尽管存在T_reg细胞，内源性干细胞样CD4 T细胞仍积极产生T_H1细胞，这是恢复TDLN效应器CD8 T细胞分化、增强肿瘤控制和免疫治疗救援反应所必需的。肾癌患者的T_H1分化预测了免疫疗法的成功反应和无进展生存率的提高。

总之，这一研究确定了一个干细胞样CD4 T细胞群，该群体通过替代分化命运控制了限制性T细胞状态和活性T细胞状态之间的转换，对癌症免疫疗法具有启示意义。

附：英文原文

Title: Differentiation fate of a stem-like CD4 T cell controls immunity to cancer

Author: Cardenas, Maria A., Prokhnevska, Nataliya, Sobierajska, Ewelina, Gregorova, Petra, Medina, Christopher B., Valanparambil, Rajesh M., Greenwald, Rachel, DelBalzo, Luke, Bilen, Mehmet Asim, Joshi, Shreyes, Naryan, Vikram, Master, Viraj A., Sanda, Martin G., Kissick, Haydn T.

Issue&Volume: 2024-10-23

Abstract: The T cell response to cancer controls disease progression and response to immunotherapy1,2,3. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1+TCF1+ CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (Treg) cells to a stem-like fate that predominantly generated induced Treg (iTreg) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into T helper 1 (TH1) cells, and via IFNγ production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as ‘active’. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Treg cells, endogenous stem-like CD4 T cells actively generated TH1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, TH1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.

DOI: 10.1038/s41586-024-08076-7

Source: https://www.nature.com/articles/s41586-024-08076-7