Wang Ling, Hensley Culton R, Rifat Jahan, Walker Adam D, Ning Katharine, Moorman Jonathan P, Yao Zhi Q, Ning Shunbin
Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
Viruses. 2025 Jun 24;17(7):885. doi: 10.3390/v17070885.
The lymphocyte-specific transcription factor interferon regulatory factor 4 (IRF4) is a key player in immune evasion in cancers, with the complex mechanism(s) being barely understood. In this study, we have focused on the role of IRF4 in regulating T cell functions through its transcriptional regulation of programmed death 1 (PD1) and its ligand PD1 ligand 1 (PD-L1), which were identified as IRF4 transcriptional targets in multi-omics analysis. We have shown that IRF4 transcriptionally regulates both PD1 and PD-L1, promoting immune suppression in the context of Epstein-Barr virus (EBV) infection. Co-culturing EBV+ JiJoye lymphoma cells with CD4+ T cells or with peripheral blood mononuclear cells (PBMCs) downregulates CD4+ T cell functions, but the depletion of IRF4 in EBV+ JiJoye lymphoma cells reduces PD1 and PD-L1 expression, and partially restores CD4+ T cell functions. Moreover, CD4+ T cell depletion from PBMCs enhances EBV transformation, and EBV has a greater efficiency in transforming PBMCs from HIV patients with impaired CD4+ T cell functions. These findings support the role of IRF4 in immune evasion by upregulating PD1/PD-L1 during EBV transformation, and that functional CD4+ T cells are essential for limiting EBV transformation.
淋巴细胞特异性转录因子干扰素调节因子4（IRF4）是癌症免疫逃逸中的关键因子，但其复杂机制仍知之甚少。在本研究中，我们聚焦于IRF4通过对程序性死亡1（PD1）及其配体PD1配体1（PD-L1）的转录调控来调节T细胞功能的作用，这两种蛋白在多组学分析中被确定为IRF4的转录靶点。我们发现，IRF4对PD1和PD-L1均具有转录调控作用，在爱泼斯坦-巴尔病毒（EBV）感染的情况下促进免疫抑制。将EBV+ JiJoye淋巴瘤细胞与CD4+ T细胞或外周血单核细胞（PBMC）共培养会下调CD4+ T细胞功能，但EBV+ JiJoye淋巴瘤细胞中IRF4的缺失会降低PD1和PD-L1的表达，并部分恢复CD4+ T细胞功能。此外，从PBMC中去除CD4+ T细胞会增强EBV转化，并且EBV在转化CD4+ T细胞功能受损的HIV患者的PBMC时效率更高。这些发现支持了IRF4在EBV转化过程中通过上调PD1/PD-L1来实现免疫逃逸的作用，以及功能性CD4+ T细胞对于限制EBV转化至关重要。
