CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Ido Somekh, Marini Thian, David Medgyesi, Nesrin Gülez, Thomas Magg, Alejandro Gallón Duque, Tali Stauber, Atar Lev, Ferah Genel, Ekrem Unal, Amos J. Simon, Yu Nee Lee, Artem Kalinichenko, Jasmin Dmytrus, Michael J. Kraakman, Ginette Schiby, Meino Rohlfs, Jeffrey M. Jacobson, Erdener Özer, Ömer AkcalRaffaele Conca, Türkan Patiroglu, Musa Karakukcu, Alper Ozcan, Tala Shahin, Eliana Appella, Megumi Tatematsu, Catalina Martinez-Jaramillo, Ivan K. Chinn, Jordan S. Orange, Claudia Milena Trujillo-Vargas, José Luis Franco, Fabian Hauck, Raz Somech, Christoph Klein, Kaan Boztug

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)- associated lymphoma.Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.

Original languageEnglish
Pages (from-to)1510-1516
Number of pages7
JournalBlood
Volume134
Issue number18
DOIs
StatePublished - 31 Oct 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 by The American Society of Hematology.

Funding

This work was supported by the European Research Council (ERC; Consolidator grant 820074 “iDysChart” [K.B.] and an ERC Advanced grant [C.K.]), the Jeffrey Modell Foundation (JMF; R.S.), the Care for Rare Foundation, the German Research Foundation (Gottfried-Wilhelm-Leibniz Program, CRC1054 [C.K.]), and the Else Kröner-Fresenius-Stiftung (Forschungskolleg Rare Diseases of the Immune System [C.K.]). I.S. was supported by the Care for Rare Foundation and has been a scholar of the Else Kröner-Fresenius-Stiftung. M. Thian was supported by a Cell Communication in Health and Disease (CCHD; Medical University of Vienna) doctoral fellowship and a DOC fellowship (25225) of the Austrian Academy of Sciences. A.G.D. was supported by a Deutscher Akademischer Austauschdienst/German Academic Exchange Service (DAAD) Fellowship (Thematic Program on Rare Diseases and Personalized Therapies). The Baylor-Hopkins Center for Mendelian Genomics was supported by the National Institutes of Health, National Human Genome Research Institute/ National Heart, Lung, and Blood Institute grant UM1HG006542. This work was supported by the European Research Council (ERC; Consolidator grant 820074 "iDysChart" [K.B.] and an ERC Advanced grant [C.K.]), the Jeffrey Modell Foundation (JMF; R.S.), the Care for Rare Foundation, the German Research Foundation (Gottfried-Wilhelm- Leibniz Program, CRC1054 [C.K.]), and the Else Kr?ner-Fresenius- Stiftung (Forschungskolleg Rare Diseases of the Immune System [C.K.]). I.S. was supported by the Care for Rare Foundation and has been a scholar of the Else Kr?ner-Fresenius-Stiftung. M. Thian was supported by a Cell Communication in Health and Disease (CCHD; Medical University of Vienna) doctoral fellowship and a DOC fellowship (25225) of the Austrian Academy of Sciences. A.G.D. was supported by a Deutscher Akademischer Austauschdienst/German Academic Exchange Service (DAAD) Fellowship (Thematic Program on Rare Diseases and Personalized Therapies). The Baylor-Hopkins Center for Mendelian Genomics was supported by the National Institutes of Health, National Human Genome Research Institute/ National Heart, Lung, and Blood Institute grant UM1HG006542.

FundersFunder number
Baylor-Hopkins
C.K.
CCHD
Care for Rare Foundation
Deutscher Akademischer Austauschdienst/German Academic Exchange ServiceTherapies
ERC advanced
Forschungskolleg Rare Diseases of the Immune System
Stiftung
National Institutes of Health
National Heart, Lung, and Blood Institute
National Human Genome Research InstituteUM1HG006542
Jeffrey Modell Foundation
California Department of Conservation25225
European Commission820074
Deutsche ForschungsgemeinschaftCRC1054
German-Israeli Foundation for Scientific Research and Development
Österreichischen Akademie der Wissenschaften
Else Kröner-Fresenius-Stiftung
Medizinische Universität Wien

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