A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency
Authors:   IRF4 International Consortium, Fornes Oriol , Jia Alicia , Kuehn Hye Sun , Min Qing , Pannicke Ulrich , Schleussner Nikolai , Thouenon Romane , Yu Zhijia , de los Angeles Astbury María , Biggs Catherine M. , Galicchio Miguel , Garcia-Campos Jorge Alberto , Gismondi Silvina , Gonzalez Villarreal Guadalupe , Hildebrand Kyla J. , Hönig Manfred , Hou Jia , Moshous Despina , Pittaluga Stefania , Qian Xiaowen , Rozmus Jacob , Schulz Ansgar S. , Staines-Boone Aidé Tamara , Sun Bijun , Sun Jinqiao , Uwe Schauer , Venegas-Montoya Edna , Wang Wenjie , Wang Xiaochuan , Ying Wenjing , Zhai Xiaowen , Zhou Qinhua , Akalin Altuna , André Isabelle , Barth Thomas F. E. , Baumann Bernd , Brüstle Anne , Burgio Gaetan , Bustamante Jacinta C. , Casanova Jean-Laurent , Casarotto Marco G. , Cavazzana Marina , Chentout Loïc , Cockburn Ian A. , Costanza Mariantonia , Cui Chaoqun , Daumke Oliver , Del Bel Kate L. , Eibel Hermann , Feng Xiaoqian , Franke Vedran , Gebhardt J. Christof M. , Götz Andrea , Grunwald Stephan , Hoareau Bénédicte , Hughes Timothy R. , Jacobsen Eva-Maria , Janz Martin , Jolma Arttu , Lagresle-Peyrou Chantal , Lai Nannan , Li Yaxuan , Lin Susan , Lu Henry Y. , Lugo-Reyes Saul O. , Meng Xin , Möller Peter , Moreno-Corona Nidia , Niemela Julie E. , Novakovsky Gherman , Perez-Caraballo Jareb J. , Picard Capucine , Poggi Lucie , Puig-Lombardi Maria-Emilia , Randall Katrina L. , Reisser Anja , Schmitt Yohann , Seneviratne Sandali , Sharma Mehul , Stoddard Jennifer , Sundararaj Srinivasan , Sutton Harry , Tran Linh Q. , Wang Ying , Wasserman Wyeth W. , Wen Zichao , Winkler Wiebke , Xiong Ermeng , Yang Ally W. H. , Yu Meiping , Zhang Lumin , Zhang Hai , Zhao Qian , Zhen Xin , Enders Anselm , Kracker Sven , Martinez-Barricarte Ruben , Mathas Stephan , Rosenzweig Sergio D. , Schwarz Klaus , Turvey Stuart E. , Wang Ji-Yang 
Published: January 2023

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.