DOI: 10.1084/jem.192.3.337. X-Linked Lymphoproliferative Disease

10.1084/jem.192.3.337

Crossref journal-article

Rockefeller University Press

The Journal of Experimental Medicine (291)

Abstract

2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1.

Bibliography

Parolini, S., Bottino, C., Falco, M., Augugliaro, R., Giliani, S., Franceschini, R., Ochs, H. D., Wolf, H., Bonnefoy, J.-Y., Biassoni, R., Moretta, L., Notarangelo, L. D., & Moretta, A. (2000). X-Linked Lymphoproliferative Disease. The Journal of Experimental Medicine, 192(3), 337â346.

Authors 13

Silvia Parolini (first)
Cristina Bottino (additional)
Michela Falco (additional)
Raffaella Augugliaro (additional)
Silvia Giliani (additional)
Roberta Franceschini (additional)
Hans D. Ochs (additional)
Hermann Wolf (additional)
Jean-Yves Bonnefoy (additional)
Roberto Biassoni (additional)
Lorenzo Moretta (additional)
Luigi D. Notarangelo (additional)
Alessandro Moretta (additional)

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 12:48 p.m.)
Deposited	2 years, 1 month ago (July 25, 2023, 6:41 a.m.)
Indexed	3 weeks, 2 days ago (Aug. 12, 2025, 6:04 p.m.)
Issued	25 years, 1 month ago (July 31, 2000)
Published	25 years, 1 month ago (July 31, 2000)
Published Online	25 years, 1 month ago (July 31, 2000)
Published Print	25 years ago (Aug. 7, 2000)

Funders 0

None

BibTeX

@article{Parolini_2000, title={X-Linked Lymphoproliferative Disease}, volume={192}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.192.3.337}, DOI={10.1084/jem.192.3.337}, number={3}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Parolini, Silvia and Bottino, Cristina and Falco, Michela and Augugliaro, Raffaella and Giliani, Silvia and Franceschini, Roberta and Ochs, Hans D. and Wolf, Hermann and Bonnefoy, Jean-Yves and Biassoni, Roberto and Moretta, Lorenzo and Notarangelo, Luigi D. and Moretta, Alessandro}, year={2000}, month=jul, pages={337–346} }

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  "abstract": "<jats:p>2B4 is a surface molecule involved in activation of the natural killer (NK) cell\u2013mediated cytotoxicity. It binds a protein termed Src homology 2 domain\u2013containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4\u2013CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4\u2013CD48 and NK receptor\u2013HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain\u2013containing phosphatase 1.</jats:p>",
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