Detuning CD8+ T lymphocytes by down-regulation of the activating receptor NKG2D: role of NKG2D ligands released by activated T cells.
NKG2D is an activating receptor expressed on CD8(+)alphabeta(+) T cells, gammadelta(+) 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.
Cerboni
Cristina
C
Department of Experimental Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy. cristina.cerboni@uniroma1.it
Ardolino
Michele
M
Santoni
Angela
A
Zingoni
Alessandra
A
D017252:CD3 Complex / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004768:Enterotoxins / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*
D017252:CD3 Complex; D004768:Enterotoxins; D015395:Histocompatibility Antigens Class I; D008024:Ligands; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma