Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency

Abstract

Background: The tumor TNF receptor family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a costimulatory signal that enhances CD8 1 T-cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB is expressed on antigen-presenting cells and EBV-transformed B cells. Objective: We investigated the genetic basis of recurrent sinopulmonary infections, persistent EBV viremia, and EBVinduced lymphoproliferation in 2 unrelated patients. Methods: Whole-exome sequencing, immunoblotting, immunophenotyping, and in vitro assays of lymphocyte and mitochondrial function were performed. Results: The 2 patients shared a homozygous G109S missense mutation in 4-1BB that abolished protein expression and ligand binding. The patients' CD8 1 T cells had reduced proliferation, impaired expression of IFN-g 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 1 Tcell activation and cytotoxicity against EBV-infected B cells in vitro. Conclusion: This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

“…Furthermore, we recently identified a familial form of CAEBV caused by digenic loss‐of‐function mutations in CD137 and PIK3CD (Rodriguez et al, submitted for publication). We showed that PIK3CD deficiency was associated with increased T cell proliferation (which might provide a cellular context for the maintenance of EBV‐infected T cells), while CD137 deficiency leads to impaired expansion of EBV‐reactive T cells (as observed in recently described CD137‐deficient patients) . These observations suggest that the pathways involved in the immune control of EBV‐infected B cells and EBV‐infected T cells may not be that different.…”

“…TNFRSF9 deficiency was reported very recently in two patients with chronic EBV viremia, B‐cell lymphoma, and HLH . Like CD27, TNFRSF9 (also known as 4‐1BB or CD137) is a member of the TNFRSF family.…”

“…Like CD27, CD137 interacts with TRAF2 and thus enhances mitochondrial activity and biogenesis in activated T cells . Analyses of CD137‐deficient T cells and the blockade of CD137 in T cells from healthy donors have highlighted (a) impaired expansion of EBV‐specific T cells in response to EBV‐infected B cells, (b) low expression of IFN‐γ and perforin, and (c) low levels of mitochondrial activity and biogenesis …”

Destroy, what destroys you

“…The mutation abolished surface expression of CD137 on activated T cells, resulting in a diminished proliferation, IFN-γ secretion, perforin expression and a reduced cytotoxic activity of CD8 + T cells upon stimulation with allogeneic and human leukocyte antigen (HLA)-matched EBV-transformed B cells. 8 Somekh et al analyzed four different patients with four distinct homozygous mutations in CD137 that reduced or abolished CD137 expression. Defects were seen in T cell activation and in the diversity of the TCR repertoire.…”

“…10 Two of the four patients analyzed by Somekh et al suffered from an EBV-related B cell lymphoma, Hodgkin's lymphoma (HL) and Burkitt's lymphoma, respectively, and one patient described by Alosaimi et al presented with HL. 8,9 One patient analyzed by Rodriguez et al suffered from EBV-associated T cell lymphoproliferative disease, and finally succumbed to hemophagocytic lymphohistiocytosis (HLH). 10 Thus, a common denominator of the three studies is that mutations in CD137 facilitate EBV-associated diseases, implying that under normal conditions CD137 limits EBV in causing pathology.…”