Submitted October 18, 2006
Accepted March 30, 2007
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 Cerboni, Alessandra Zingoni*, Marco Cippitelli, Mario Piccoli, Luigi Frati, and Angela Santoni
Dept of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, University "La Sapienza", Rome, Italy
Regina Elena Cancer Institute, Rome, Italy
Istituto Mediterraneo di Neuroscienze "Neuromed", Pozzilli, Italy
* Corresponding author; email: alessandra.zingoni{at}uniroma1.it.
Recent evidences indicate that NK cells can negatively regulate T cell responses, but the mechanisms behind this phenomenon as consequence of NK-T cell interaction are rather unknown. We studied the NKG2D/NKG2D ligands (NKG2DLs) interaction, and asked whether T cells in response to superantigen, alloantigen or a specific antigenic peptide expressed NKG2DLs and if this rendered them susceptible to NK lysis. As evaluated by FACS, MICA was the ligand expressed earlier on both CD4+ and CD8+ T cells in 90% of the donors tested, while ULBP1, 2, and 3 were induced at later times in 55-75% of the donors. By CFSE labelling, we observed that NKG2DLs were expressed mainly on T cells that had gone through at least one division. Real-time RT-PCR confirmed the expression of all NKG2DLs, except ULBP4. In addition, T cell activation stimulated phosphorylation of ATM, a kinase required for NKG2DLs expression following DNA damage, and ATM/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.
