Detuning CD8( ) T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells

作者：Cerboni Cristina^*; Ardolino Michele; Santoni Angela; Zingoni Alessandra

来源：Blood, 2009, 113(13): 2955-2964.

DOI：10.1182/blood-2008-06-165944

NKG2D is an activating receptor expressed on CD8( )alpha beta( ) T cells, alpha beta( ) T cells, natural killer (NK) cells, and some CD4( ) T cells. For a long time, the interaction of NKG2D with its ligands (NKG2DLs) MICA, MICB, and ULBP1-3 has been considered a mechanism for recognition and elimination of tumor, infected, or otherwise "stressed" cells. However, a new role for NKG2D as an immunoregulatory receptor is emerging. Here, we show that NKG2D is strongly down-modulated on antigen-activated CD8( ) T cells but only if CD4( ) T cells are present. Down-modulation was caused by soluble factors produced by CD4( ) T cells, and in particular soluble NKG2DLs were found in the supernatants of antigen-activated T-cell cultures. MICB was the ligand released at higher levels when CD4( ) T cells were present in the cell cultures, suggesting that it could be the major player of NKG2D down-modulation. CD8( ) T cells expressing low levels of NKG2D had impaired effector functions, as evaluated by proliferation, cytokine production, and cytotoxicity assays after combined triggering of NKG2D and TCR-CD3 complex. These findings show that activated CD4( ) T cells expressing NKG2DLs can efficiently prevent NKG2D-mediated CD8( ) T-cell functions, and suggest that the NKG2D/NKG2DL interaction can regulate immune responses. (Blood. 2009; 113: 2955-2964)

• 出版日期2009-3-26