Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4T95R. Simultaneously, IRF4T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4T95R but not by IRF4WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

中文翻译：

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IRF4 的多态性突变导致人类常染色体显性联合免疫缺陷。

干扰素调节因子 4 (IRF4) 是一种转录因子 (TF)，是免疫细胞发育和功能的关键调节因子。我们报告了 IRF4 中反复发生的杂合突变，p.T95R，导致来自 6 个无关家庭的 7 名患者出现常染色体显性联合免疫缺陷 (CID)。这些患者对机会性感染表现出极度易感性，尤其是耶氏肺孢子菌，并出现丙种球蛋白血症。患者的 B 细胞显示成熟受损、免疫球蛋白同种型转换减少和浆细胞分化缺陷，而他们的 T 细胞含有减少的 TH17 和 TFH 细胞群，并表现出细胞因子产生减少。杂合子 T95R 的基因敲入小鼠模型在稳定状态下和用不同类型的抗原免疫后均显示出抗体产生的严重缺陷，这与在这些患者中观察到的 CID 一致。IRF4T95R 变体映射到 TF 的 DNA 结合域，改变其典型的 DNA 结合特异性，并导致 IRF4 的损失、获得和新功能的同时多态性组合。IRF4T95R 通过以比 IRF4WT 更高的亲和力与 DNA 结合，表现为功能获得超形态。尽管对 DNA 的亲和力增加，IRF4 经典基因的转录活性降低，显示出 IRF4T95R 的亚形态活性。同时，IRF4T95R 通过与非规范 DNA 位点结合来改变基因表达谱，从而发挥新变体的作用，包括仅由 IRF4T95R 而不是 IRF4WT 诱导的基因转录。这种以前未描述的多态性 IRF4 病理生理学破坏了正常的淋巴细胞生物学，导致人类疾病。