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Blood, 15 July 2007, Vol. 110, No. 2, pp. 606-615.
Prepublished online as a Blood First Edition Paper on April 3, 2007; DOI 10.1182/blood-2006-10-052720.
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IMMUNOBIOLOGY
Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis
Cristina Cerboni1,
Alessandra Zingoni1,
Marco Cippitelli1,2,
Mario Piccoli1,
Luigi Frati1,3, and
Angela Santoni1,2
1 Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome;
2 Regina Elena Cancer Institute, Rome;
3 Istituto Mediterraneo di Neuroscienze Neuromed, Pozzilli, Italy
Recent evidence indicates that natural killer (NK) cells can negatively regulate T-cell responses, but the mechanisms behind this phenomenon as a consequence of NK–T-cell interactions are poorly understood. We studied the interaction between the NKG2D receptor and its ligands (NKG2DLs), and asked whether T cells expressed NKG2DLs in response to superantigen, alloantigen, or a specific antigenic peptide, and if this rendered them susceptible to NK lysis. As evaluated by FACS, the major histocompatibility complex (MHC) class I chain-related protein A (MICA) was the ligand expressed earlier on both CD4+ and CD8+ T cells in 90% of the donors tested, while UL16-binding protein-1 (ULBP)1, ULBP2, and ULBP3 were induced at later times in 55%–75% of the donors. By carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, we observed that NKG2DLs were expressed mainly on T cells that had gone through at least one division. Real-time reverse-transcription polymerase chain reaction confirmed the expression of all NKG2DLs, except ULBP4. In addition, T-cell activation stimulated phosphorylation of ataxia-telangiectasia mutated (ATM), a kinase required for NKG2DLs expression after DNA damage, and ATM/Rad3-related kinase (ATR) inhibitors blocked MICA induction on T cells with a mechanism involving NF- B. Finally, we demonstrated that activated T cells became susceptible to autologous NK lysis via NKG2D/NKG2DLs interaction and granule exocytosis, suggesting that NK lysis of T lymphocytes via NKG2D may be an additional mechanism to limit T-cell responses.
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