Induction of antigen-specific human CD4(+) T cell anergy by peripheral blood DC2 precursors.
Dendritic cells (DC) are antigen (Ag)-presenting cells that are essential for initiation of T cell-dependent immunity, and distinct DC subsets are known to direct different classes of immune responses. DC2 precursors (pDC2) or plasmacytoid DC were recently identified as a Th2-skewing and IFN-alpha-producing human DC subset. Here, we demonstrate that pDC2 enriched from human peripheral blood have a capacity to induce an anergic state in human Ag-specific CD4(+) T cell lines. Tetanus toxoid-specific T cell lines incubated with tetanus toxoid-pulsed autologous pDC2 failed to proliferate in secondary cultures with optimal Ag stimulation. T cell anergy induction required TCR engagement with Ag/MHC complex presented on pDC2. T cells rendered anergic lost IL-2 production but produced IFN-gamma and IL-10 upon stimulation. The pDC2-induced unresponsiveness was completely or partially reversible when a high concentration of exogenous IL-2 was added in the secondary cultures. Autoreactive CD4(+) T cell clones specific for topoisomerase I derived from a patient with scleroderma were also rendered anergic after co-culture with topoisomerase I-pulsed autologous pDC2,resulting in failure to proliferate or provide help to B cells. These results suggest that pDC2 are involved in maintenance of peripheral T cell tolerance and have potential for use in the suppression of pathogenic T cell responses in autoimmune diseases and organ transplantation.
Kuwana
M
M
Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. kuwanam@sc.itc.keio.ac.jp
Kaburaki
J
J
Wright
T M
TM
Kawakami
Y
Y
Ikeda
Y
Y
D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001769:Blood / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D017635:Clonal Anergy; D016207:Cytokines / Q000096:biosynthesis; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D017634:Self Tolerance; D013234:Stem Cells / Q000276:immunology; D013745:Tetanus Toxoid / Q000276:immunology
D001324:Autoantigens; D016207:Cytokines; D007376:Interleukin-2; D013745:Tetanus Toxoid; D004264:DNA Topoisomerases, Type I