Antigen-specific induced T regulatory cells impair dendritic cell function via an IL-10/MARCH1-dependent mechanism.
Foxp3(+) T regulatory cells (Tregs) are critically important for the maintenance of immunological tolerance, immune homeostasis, and prevention of autoimmunity. Dendritic cells (DCs) are one of the major targets of Treg-mediated suppression. Some studies have suggested that Treg-mediated suppression of DC function is mediated by the interaction of CTLA-4 on Tregs with CD80/CD86 on the DCs resulting in downregulation of CD80/CD86 expression and a decrease in costimulation. We have re-examined the effects of Tregs on mouse DC function in a model in which Ag-specific, induced Tregs (iTregs) are cocultured with DCs in the absence of T effector cells. iTreg-treated DCs are markedly defective in their capacity to activate naive T cells. iTregs from CTLA-4-deficient mice failed to induce downregulation of CD80/CD86, but DCs treated with CTLA-4-deficient iTregs still exhibited impaired capacity to activate naive T cells. The iTreg-induced defect in DC function could be completely reversed by anti-IL-10, and IL-10-deficient iTregs failed to downregulate DC function. iTreg-treated DCs expressed high levels of MARCH1, an E3 ubiquitin ligase, recently found to degrade CD86 and MHC class II on the DCs and expressed lower levels of CD83, a molecule involved in neutralizing the function of MARCH1. Both the enhanced expression of MARCH1 and the decreased expression of CD83 were mediated by IL-10 produced by the iTregs. Taken together, these studies demonstrate that a major suppressive mechanism of DC function by iTregs is secondary to the effects of IL-10 on MARCH1 and CD83 expression.
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Gouri
G
Chattopadhyay
Ethan M
EM
Shevach
D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000172:deficiency / Q000502:physiology; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000172:deficiency; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007136:Immunoglobulins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000096:biosynthesis; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000097802:CD83 Antigen
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D016753:Interleukin-10; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases; D000097802:CD83 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; C556062:IL10 protein, mouse; C499308:Rag2 protein, mouse; C545340:MARCH1 protein, mouse