XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells |
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| Authors: | Raffaella Meazza Claudia Tuberosa Valentina Cetica Michela Falco Fabrizio Loiacono Silvia Parolini Concetta Micalizzi Alessandro Moretta Maria C. Mingari Lorenzo Moretta Cristina Bottino Maurizio Aricò Daniela Pende |
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| Affiliation: | 1. Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino‐Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy;2. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy;3. Azienda Ospedaliero‐Universitaria Meyer, Dipartimento di Oncoematologia Pediatrica, Florence, Italy;4. Istituto Toscano Tumori (I.T.T.), Florence, Italy;5. Istituto Giannina Gaslini, Genoa, Italy;6. Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia, Brescia, Italy |
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| Abstract: | X‐linked lymphoproliferative disease 1 (XLP1) is a rare congenital immunodeficiency caused by SH2D1A (Xq25) mutations resulting in lack or dysfunction of SLAM‐associated protein adaptor molecule. In XLP1 patients, upon ligand (CD48) engagement, 2B4 delivers inhibitory signals that impair the cytolytic activity of NK (and T) cells. This causes the selective inability to control EBV infections and the occurrence of B‐cell lymphomas. Here, we show that in the absence of SLAM‐associated protein, co‐engagement of 2B4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM‐dependent signaling pathways including activating killer Ig‐like receptors. In XLP1 NK cells, 2B4 affected both the cytolytic and IFN‐γ production capabilities, functions that were restored upon disruption of the 2B4/CD48 interactions. Notably, we provide evidence that 2B4 dysfunction does not affect the activity of DNAM‐1 and NKG2D triggering receptors. Thus, while CD48+ B‐EBV and lymphoma B cells devoid of NKG2D and DNAM‐1 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP1 NK cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP1 immunological defect and on the cross‐talk of inhibitory 2B4 with triggering NK (and T) receptors. |
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| Keywords: | 2B4 Ligands NK cells Triggering receptors XLP1 |
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