A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency

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Item Type:	Article
Title:	A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency
Creators Name:	Fornes, O., Jia, A., Kuehn, H.S., Min, Q., Pannicke, U., Schleussner, N., Thouenon, R., Yu, Z., de Los Angeles Astbury, M., Biggs, C.M., Galicchio, M., Garcia-Campos, J.A., Gismondi, S., Gonzalez Villarreal, G., Hildebrand, K.J., Hönig, M., Hou, J., Moshous, D., Pittaluga, S., Qian, X., Rozmus, J., Schulz, A.S., Staines-Boone, A.T., Sun, B., Sun, J., Uwe, S., Venegas-Montoya, E., Wang, W., Wang, X., Ying, W., Zhai, X., Zhou, Q., Akalin, A., André, I., Barth, T.F.E., Baumann, B., Brüstle, A., Burgio, G., Bustamante, J.C., Casanova, J.L., Casarotto, M.G., Cavazzana, M., Chentout, L., Cockburn, I.A., Costanza, M., Cui, C., Daumke, O., Del Bel, K.L., Eibel, H., Feng, X., Franke, V., Gebhardt, J.C.M., Götz, A., Grunwald, S., Hoareau, B., Hughes, T.R., Jacobsen, E.M., Janz, M., Jolma, A., Lagresle-Peyrou, C., Lai, N., Li, Y., Lin, S., Lu, H.Y., Lugo-Reyes, S.O., Meng, X., Möller, P., Moreno-Corona, N., Niemela, J.E., Novakovsky, G., Perez-Caraballo, J.J., Picard, C., Poggi, L., Puig-Lombardi, M.E., Randall, K.L., Reisser, A., Schmitt, Y., Seneviratne, S., Sharma, M., Stoddard, J., Sundararaj, S., Sutton, H., Tran, L.Q., Wang, Y., Wasserman, W.W., Wen, Z., Winkler, W., Xiong, E., Yang, A.W.H., Yu, M., Zhang, L., Zhang, H., Zhao, Q., Zhen, X., Enders, A., Kracker, S., Martinez-Barricarte, R., Mathas, S., Rosenzweig, S.D., Schwarz, K., 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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