Mohammed F. Alosaimi, United States of America
Boston Children Hospital ImmunologyPresenter of 1 Presentation
IMMUNODEFICIENCY AND EPSTEIN BARR VIRUS INDUCED LYMPHOPROLIFERATION CAUSED BY 4-1BB DEFICIENCY
Abstract
Background and Aims
The tumor necrosis family factor receptor (TNFR) family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a co-stimulatory signal that enhances CD8+ T cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB (4-1BBL) is expressed on antigen-presenting cells and Epstein-Barr virus (EBV) transformed B cells. We investigated the genetic basis of recurrent sino-pulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in two unrelated patients.
Methods
Whole exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed.
Results
The two patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. Patient 1 presented with EBV driven haemophagocytic lymphohistiocytosis. Patient 2 presented with relapsing EBV associated lymphomas. The patients’ CD8+ T cells had reduced proliferation, impaired expression of interferon-γ (IFN-γ) and perforin, and diminished cytotoxicity against allogeneic and HLA matched EBV-B cells. Mitochondrial biogenesis, membrane potential, and function were significantly reduced in the patients’ activated T cells. An inhibitory antibody against 4-1BB recapitulated the patients’ defective CD8+ T cell activation and cytotoxicity against EBV-infected B cells in vitro.
Conclusions
This novel immunodeficiency demonstrates the critical role of 4-1BB co-stimulation in host immunity against EBV infection.