title: Delayed type hypersensitivity-induced myeloid-derived suppressor cells regulate autoreactive T cells.
abstract: Mild but efficient treatments of autoimmune diseases are urgently required. One such therapy, long-term maintenance of chronic delayed type hypersensitivity, has been described for alopecia areata (AA), a hair follicle-affecting autoimmune disease. The molecular mechanisms underlying the therapeutic efficacy are unknown, but may involve myeloid-derived suppressor cells (MDSCs). AA-affected mice were treated with squaric acid dibutyl ester (SADBE). The immunoreactivity of SADBE-treated AA lymphocytes and of AA lymphocytes co-cultured with SADBE-induced MDSCs was analyzed. The curative effect of SADBE was abolished by all-transretinoic acid, which drives MDSCs into differentiation, confirming a central role for MDSCs in therapeutic SADBE treatment. SADBE and SADBE-induced MDSCs strongly interfered with sustained autoreactive T-cell proliferation in response to AA skin lysate (autoantigen), which was accompanied by weak ζ-chain down-regulation and strongly impaired Lck activation. In contrast, activation of the mitochondrial apoptosis pathway and blockade of the anti-apoptotic PI3K/Akt pathway by SADBE-induced MDSCs did not require T-cell receptor engagement. Apoptosis induction correlated with high TNF-α expression in SADBE-induced MDSCs and elevated TNFRI levels in AA lymphocytes. SADBE-induced MDSCs interfere with persisting autoreactive T-cell proliferation and promote apoptosis of these T cells, which qualifies MDSCs induced and maintained by chronic delayed type hypersensitivity reactions as promising therapeutics in organ-related autoimmune diseases.
authors: Department of Tumor Cell Biology, University Hospital of Surgery, Heidelberg, Germany.
authors: Vibhuti
authors: V
authors: Singh
authors: Ulrike
authors: U
authors: Mueller
authors: Pia
authors: P
authors: Freyschmidt-Paul
authors: Margot
authors: M
authors: Zöller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000506:Alopecia Areata / Q000188:drug therapy* / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D016516:CD4-CD8 Ratio; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003503:Cyclobutanes / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008928:Mitochondria / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003503:Cyclobutanes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; C402726:Sh2d2a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C020637:squaric acid dibutyl ester; D014212:Tretinoin; D051057:Proto-Oncogene Proteins c-akt