A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

Item Type:	Article
Title:	A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency
Creators Name:	Fornes, O. and Jia, A. and Kuehn, H.S. and Min, Q. and Pannicke, U. and Schleussner, N. and Thouenon, R. and Yu, Z. and de Los Angeles Astbury, M. and Biggs, C.M. and Galicchio, M. and Garcia-Campos, J.A. and Gismondi, S. and Gonzalez Villarreal, G. and Hildebrand, K.J. and Hönig, M. and Hou, J. and Moshous, D. and Pittaluga, S. and Qian, X. and Rozmus, J. and Schulz, A.S. and Staines-Boone, A.T. and Sun, B. and Sun, J. and Uwe, S. and Venegas-Montoya, E. and Wang, W. and Wang, X. and Ying, W. and Zhai, X. and Zhou, Q. and Akalin, A. and André, I. and Barth, T.F.E. and Baumann, B. and Brüstle, A. and Burgio, G. and Bustamante, J.C. and Casanova, J.L. and Casarotto, M.G. and Cavazzana, M. and Chentout, L. and Cockburn, I.A. and Costanza, M. and Cui, C. and Daumke, O. and Del Bel, K.L. and Eibel, H. and Feng, X. and Franke, V. and Gebhardt, J.C.M. and Götz, A. and Grunwald, S. and Hoareau, B. and Hughes, T.R. and Jacobsen, E.M. and Janz, M. and Jolma, A. and Lagresle-Peyrou, C. and Lai, N. and Li, Y. and Lin, S. and Lu, H.Y. and Lugo-Reyes, S.O. and Meng, X. and Möller, P. and Moreno-Corona, N. and Niemela, J.E. and Novakovsky, G. and Perez-Caraballo, J.J. and Picard, C. and Poggi, L. and Puig-Lombardi, M.E. and Randall, K.L. and Reisser, A. and Schmitt, Y. and Seneviratne, S. and Sharma, M. and Stoddard, J. and Sundararaj, S. and Sutton, H. and Tran, L.Q. and Wang, Y. and Wasserman, W.W. and Wen, Z. and Winkler, W. and Xiong, E. and Yang, A.W.H. and Yu, M. and Zhang, L. and Zhang, H. and Zhao, Q. and Zhen, X. and Enders, A. and Kracker, S. and Martinez-Barricarte, R. and Mathas, S. and Rosenzweig, S.D. and Schwarz, K. and Turvey, S.E. and Wang, J.Y.
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 TH(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.
Keywords:	B-Lymphocytes, DNA, Gene Expression Regulation, Interferon Regulatory Factors, Mutation, Animals, Mice
Source:	Science Immunology
ISSN:	2470-9468
Publisher:	American Association for the Advancement of Science
Volume:	8
Number:	79
Page Range:	eade7953
Date:	January 2023
Additional Information:	Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Official Publication:	https://doi.org/10.1126/sciimmunol.ade7953
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