A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

Abstract

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 T H 17 and T FH 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 IRF4 T95R 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. IRF4 T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4 WT . Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4 T95R . Simultaneously, IRF4 T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4 T95R but not by IRF4 WT . This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Inborn errors of human B cell development, differentiation, and function

“…2 and 4 ). Notably, cTfh cells are also reduced in patients with the IRF4 T95R variant ( International Consortium et al, 2023 ), confirming a role for IRF in Tfh generation ( Fig. 3 ).…”

“…A novel IEI was recently reported in seven individuals from six families due to a recurrent heterozygous IRF4 variant (IRF4 T95R ; International Consortium et al, 2023 ). These patients had opportunistic infections, agammaglobulinemia, and a severe deficiency of memory B cells and PC.…”

“…These patients had opportunistic infections, agammaglobulinemia, and a severe deficiency of memory B cells and PC. Patient naive B cells were unable to undergo CSR and PC differentiation in vitro, establishing that B cell–intrinsic effects of IRF4 T95R contributed to their humoral defects ( International Consortium et al, 2023 ). IL-21 induces IRF4 expression in activated B cells ( Deenick et al, 2013 ; Luo et al, 2023 ), and IRF4 upregulates AID and promotes CSR and PC generation in vivo in an IL-21–dependent manner ( Klein et al, 2006 ; Luo et al, 2023 ).…”

Human inborn errors of immunity associated with IRF4

“…Interestingly, Irf4 T95R knock-in mice indicated an expansion of nonspecific germinal center B cells at the expense of antigen-specific germinal center B cells. Consistent with an increased affinity for DNA, the subcellular localization of IRF4 T95R was altered, with an increased nuclear-to-cytoplasmic ratio compared with IRF4 wild type ( 74 ). CHIP-Seq analysis performed on patients’ derived B-EBV cells in conjunction with a deep learning tool (ExplaiNN) ( 75 ) unveiled IRF4 T95R -altered DNA binding specificity.…”

“…Seven patients were found around the world all presenting with early-onset (<1 year of age) recurrent sinopulmonary infections associated with agammaglobulinemia and a lack of circulating plasma cells even though circulating B cells were found ( 74 ). Six out of the seven patients suffered from Pneumocystis jirovecii , causing pneumonia.…”