KIR expression on self-reactive CD8+ T cells is controlled by T-cell receptor engagement.
Natural killer cell tolerance is maintained by the interaction of killer inhibitory receptors (KIRs) with self-major histocompatibility complex class I gene products. A subset of T cells also expresses inhibitory receptors, but the functional significance of these receptors on T cells is unclear. Here we show that, in the absence of T-cell receptor (TCR) engagement, KIRs expressed on CD8+ T cells are slowly downregulated by KIR ligands expressed on antigen-presenting cells. The resulting expression levels of KIR are no longer able to inhibit T-cell function. In contrast, TCR engagement sustains KIR expression, and re-induces functional levels of KIR expression after ligand-induced downregulation of KIR. Our data indicate that KIR expression on CD8+ T cells in vivo may be maintained through continuous encounters with antigen. As KIR-mediated inhibition of T-cell activation can be bypassed at high antigen concentrations, dynamic KIR expression may mediate T-cell tolerance to self-antigens by sparing self-reactive T cells, thus enabling them to mediate potentially useful immune functions to quantitatively or qualitatively different antigens.
Huard
B
B
The R.W. Johnson Pharmaceutical Research Institute, San Diego, California 92121, USA. huard@cmu.unige.ch
Karlsson
L
L
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D015236:HLA-C Antigens / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation; D018942:Macrolides; D014442:Monophenol Monooxygenase / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D054340:Receptors, KIR; D017634:Self Tolerance
D000900:Anti-Bacterial Agents; D015236:HLA-C Antigens; C040178:HLA-C*70 antigen; D008024:Ligands; D018942:Macrolides; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D007371:Interferon-gamma; C040929:bafilomycin A1; D014442:Monophenol Monooxygenase