Abstract
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.
Publication types
-
Research Support, N.I.H., Intramural
MeSH terms
-
Animals
-
Antigen Presentation
-
Antigens, CD / biosynthesis
-
Antigens, CD / genetics
-
Antigens, CD / physiology*
-
B7-1 Antigen / biosynthesis
-
B7-1 Antigen / genetics
-
B7-2 Antigen / biosynthesis
-
B7-2 Antigen / genetics
-
CD4-Positive T-Lymphocytes / immunology
-
CD83 Antigen
-
CTLA-4 Antigen / deficiency
-
CTLA-4 Antigen / physiology
-
Cell Separation
-
Cells, Cultured
-
Coculture Techniques
-
DNA-Binding Proteins / deficiency
-
Dendritic Cells / immunology*
-
Epitopes, T-Lymphocyte / immunology*
-
Flow Cytometry
-
Gene Expression Regulation / immunology*
-
Histocompatibility Antigens Class II / immunology
-
Immune Tolerance / immunology*
-
Immunoglobulins / biosynthesis
-
Immunoglobulins / genetics
-
Immunoglobulins / physiology*
-
Interleukin-10 / antagonists & inhibitors
-
Interleukin-10 / deficiency
-
Interleukin-10 / metabolism
-
Interleukin-10 / physiology*
-
Lymphocyte Activation
-
Membrane Glycoproteins / biosynthesis
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / physiology*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, Transgenic
-
RNA, Messenger / biosynthesis
-
T-Cell Antigen Receptor Specificity*
-
T-Lymphocytes, Regulatory / immunology*
-
T-Lymphocytes, Regulatory / metabolism
-
Ubiquitin-Protein Ligases / biosynthesis
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / physiology*
Substances
-
Antigens, CD
-
B7-1 Antigen
-
B7-2 Antigen
-
CTLA-4 Antigen
-
Cd86 protein, mouse
-
Ctla4 protein, mouse
-
DNA-Binding Proteins
-
Epitopes, T-Lymphocyte
-
Histocompatibility Antigens Class II
-
IL10 protein, mouse
-
Immunoglobulins
-
Membrane Glycoproteins
-
RNA, Messenger
-
Rag2 protein, mouse
-
Interleukin-10
-
MARCH1 protein, mouse
-
Ubiquitin-Protein Ligases