The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema.
Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4(+)CD25(high) lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4(+)CD25(+) T cells. Instead, a population of Gr-1(+)CD11b(+) cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1(+)CD11b(+) spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-gamma receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1(+) cells expressed several chemokines and CCR8 at high levels. Gr-1(+)CD11b(+) cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4(+) or CD8(+) cells from AA mice, the Gr-1(+)CD11b(+) cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, zeta-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via zeta-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.
Marhaba
Rachid
R
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany.
Vitacolonna
Mario
M
Hildebrand
Dagmar
D
Baniyash
Michal
M
Freyschmidt-Paul
Pia
P
Zöller
Margot
M
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000506:Alopecia Areata / Q000276:immunology / Q000473:pathology; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002908:Chronic Disease; D003503:Cyclobutanes / Q000008:administration & dosage / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015536:Down-Regulation / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D000485:Allergens; D003503:Cyclobutanes; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; C020637:squaric acid dibutyl ester