A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

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 pro-found susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agamma-globulinemia. 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 IRF4'. Despite this increased affinity for DNA, the transcriptional activity on IRF4 ca-nonical 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 tran-scription of genes exclusively induced by IRF4T95R but not by IRF4'. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Automated summary

A recurrent heterozygous mutation in IRF4 has been found to cause autosomal dominant combined immunodeficiency. This mutation leads to severe susceptibility to opportunistic infections, including Pneumocystis jirovecii, and agamma-globulinemia. The pathophysiology of this mutation disrupts normal lymphocyte biology through multimorphic changes in the function of IRF4.