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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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
Issue number18
StatePublished - 31 Oct 2019


FundersFunder number
Care for Rare Foundation
Deutscher Akademischer Austauschdienst/German Academic Exchange ServiceTherapies
ERC advanced
Forschungskolleg Rare Diseases of the Immune System
National Institutes of Health
National Heart, Lung, and Blood Institute
National Human Genome Research InstituteUM1HG006542
Jeffrey Modell Foundation
California Department of Conservation25225
European Research Council820074
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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