Detuning CD8 + T lymphocytes by down-regulation of the activating receptor NKG2D: Role of NKG2D ligands released by activated T cells

Cristina Cerboni, Michele Ardolino, Angela Santoni, Alessandra Zingoni

Research output: Contribution to journalArticle

Abstract

NKG2D is an activating receptor expressed on CD8 +αβ+ T cells, γδ + 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 considereda 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 func-tions, 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.

Original languageEnglish
Pages (from-to)2955-2964
Number of pages10
JournalBlood
Volume113
Issue number13
DOIs
Publication statusPublished - Mar 26 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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