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The Importance of Myeloid-Derived Suppressor Cells in the Regulation of Autoimmune Effector Cells by a Chronic Contact Eczema¹

Rachid Marhaba^*, Mario Vitacolonna^*, Dagmar Hildebrand^*, Michal Baniyash, Pia Freyschmidt-Paul and Margot Zöller^2,*,

^* Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany; Department of Applied Genetics, University of Karlsruhe, Germany; Lautenberg Center for General and Tumor Immunology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel; and Department of Dermatology, Philipps University Hospital, Marburg, Germany

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- 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, -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 -chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grant FR1509/1-2 (to P.F.P.) and Zo40/9-1 (to M.Z.).

² Address correspondence and reprint requests to Dr. Margot Zöller, Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, Germany. E-mail address: m.zoeller{at}dkfz.de

³ Abbreviations used in this paper: T_reg, regulatory T cell; AA, alopecia areata; AA/DTH mice, SADBE-treated AA-affected mice; DTH, delayed-type hypersensitivity; LNC, lymph node cell; M, macrophage; MDSC, myeloid-derived suppressor cell; PARP, poly(ADP-ribose) polymerase; SADBE, squaric acid dibutyl ester; SkIL, skin infiltrating leukocyte; SC, spleen cell; TNFRI, TNF receptor I.