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 Akcal, Raffaele 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 and Kaan Boztug

Key Points

  • CD137 deficiency is a novel inborn error of immunity with immune dysregulation and EBV-associated lymphomagenesis

  • Our study highlights the key role of CD137 for immune homeostasis with relevance to immunodeficiency and cancer immunotherapy


Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity and immunodeficiency. We here investigated four patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified four distinct homozygous mutations in TNFRSF9 encoding the Tumor Necrosis Factor 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.

  • Submitted March 17, 2019.
  • Revision received August 20, 2019.
  • Accepted September 2, 2019.