Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency - 05/08/19

Doi : 10.1016/j.jaci.2019.03.002

Mohammed F. Alosaimi, MD ^a,^b, Manfred Hoenig, MD ^c, Faris Jaber, MD ^a, Craig D. Platt, MD, PhD ^a, Jennifer Jones, BA ^a, Jacqueline Wallace, BSPH ^a, Klaus-Michael Debatin, MD ^c, Ansgar Schulz, MD ^c, Eva Jacobsen, PhD ^c, Peter Möller, MD ^d, Hanan E. Shamseldin, MSc ^e, Ferdous Abdulwahab, MSc ^e, Niema Ibrahim, MD ^e, Hosam Alardati, MD ^f, Faisal Almuhizi, MD ^g, Ibraheem F. Abosoudah, MD ^h, Talal A. Basha, MD ⁱ, Janet Chou, MD ^a,^{∗
These authors contributed equally to this work.}, Fowzan S. Alkuraya, MD ^e,^{∗
These authors contributed equally to this work.}, Raif S. Geha, MD ^a,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Mass
^b Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia
^c Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
^d Institute of Pathology, University of Ulm, Ulm, Germany
^e Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^f Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
^g Department of Medicine, Security Force Hospital, Riyadh, Saudi Arabia
^h Department of Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
ⁱ Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia

^∗Corresponding author: Raif S. Geha, MD, Division of Immunology, Boston Children's Hospital, 1 Blackfan Circle, Karp Building 10^th floor, Boston, MA 02115.Division of ImmunologyBoston Children's Hospital1 Blackfan Circle, Karp Building 10^th floorBostonMA02115

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⁺ 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 EBV-induced 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⁺ T cells had reduced proliferation, impaired expression of 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.

Conclusion

This novel immunodeficiency demonstrates the critical role of 4-1BB costimulation in host immunity against EBV infection.

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Key words : 4-1BB, CD137, immunodeficiency, EBV, Hodgkin lymphoma

Abbreviations used : APC, 4-1BBL, CRD, E/T, FITC, NK, OCR, PE, ROH, SNP, TNFR

Plan

4-1BB and 4-1BBL expression and 4-1BBL binding

Immunoblotting

Intracellular cytokine staining

Cytotoxic T-cell generation and killing assay

Oxygen consumption

Mitochondrial studies

Statistics

Results

Two patients with immunodeficiency and EBV lymphoproliferation

Defective expansion, reduced expression of IFN-γ and perforin, and impaired allospecific and EBV-specific cytotoxic activity of patients' CD8⁺ T cells

Defective mitochondrial biogenesis and function in the patients' activated T cells

Discussion

	Supported by National Institutes of Health grants 5K08AI116979-04 (to J.C.) and 1R01AI139633-01 (to R.S.G.) and the Perkin Fund (to R.S.G.). This work was supported in part by King Salman Center for Disability Research and the Saudi Human Genome Program.
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 144 - N° 2

P. 574 - août 2019 Retour au numéro

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Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency - 05/08/19

Abstract

Background

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Results

Conclusion

Plan

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