CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis

Blood. 2019 Oct 31;134(18):1510-1516. doi: 10.1182/blood.2019000644.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Lymphoma / genetics*
  • Lymphoma / immunology
  • Male
  • Pedigree
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics*


  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9