Muller morphs redefined by a multimorphic IRF4 variant presenting as CID with PCP susceptibility

In their last review, the IUIS reported 40 inborn errors of immunity (IEI) leading to combined immunodeficiency (CID). Yet, the genetic cause of CID in a sizeable percentage of patients remains unknown. We describe seven patients with CID from four continents with similar clinical presentations characterized by severe viral and recurrent respiratory infections, notably by Pneumocystis jirovecii. Two of the patients also suffered from mycobacterial disease. All these seven patients carry the heterozygous mutation T95R in the DNA binding domain of the interferon regulatory factor 4 (IRF4). Leveraging state-of-the-art transcriptomic, molecular, computational, and gene editing technologies, we discovered that IRF4-T95R does not fit into any single category of the Muller morphs but in three of them simultaneously. In fact, we showed that IRF4-T95R causes a unique combination of (i) gain-of-function by binding DNA with higher affinity than IRF4-WT; (ii) loss-of-function since IRF4-T95R fails to induce canonical IRF4 regulated genes, and; (iii) neomorphic functions by inducing the transcription of genes that IRF4-WT does not. These alterations in the transcriptional programming caused by the mutation lead to cellular and humoral immunological abnormalities. Patients’ B cells displayed impaired maturation, defective plasma cell differentiation, and isotype switching, all which resulted in agammaglobulinemia. Their T cells, despite proliferating normally, showed a decreased production of pro-inflammatory cytokines and a reduced capacity to differentiate into TH17 and TFH. Two different knock-in mouse models recapitulated the patients’ phenotypes. Overall, our data show that autosomal dominant IRF4-T95R is a new genetic cause of CID and defines a novel multimorphic molecular mechanism of a disease characterized by gain, loss, and new functions of IRF4.