Abstract
Naturally occurring CD4+CD25+ regulatory T (TR) cells play crucial roles in normal immunohomeostasis. CD4+CD25+ TR cells exhibit a number of interesting in vitro properties including a 'default state' of profound anergy refractory to conventional T cell stimuli. We investigated the in vitro activation requirements of CD4+CD25+ TR cells using bone marrow-derived DC, which as professional antigen presenting cells (APC) can support the activation of normal naive T cells. Comparison of different APC types revealed that LPS-matured DC were by far the most effective at breaking CD4+CD25+ TR cell anergy and triggering proliferation, and importantly their IL-2 production. Examination of Foxp3, a key control gene for CD4+CD25+ TR cells, showed this to be stably expressed even during active proliferation. Although CD4+CD25+ TR cell proliferation was equivalent to that of CD25- cells their IL-2 production was considerably less. Use of IL-2-/- mice demonstrated that the DC stimulatory ability was not dependent on IL-2 production; nor did IL-15 appear crucial but was, at least in part, related to costimulation. DC also blocked normal CD4+CD25+ TR cell-mediated suppression partially via IL-6 secretion. DC therefore possess novel mechanisms to control the suppressive ability, expansion and/or differentiation of CD4+CD25+ TR cells in vivo.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / pharmacology
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Antigens, CD / physiology
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B7-2 Antigen
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / physiology
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CD4 Antigens / immunology
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Clonal Anergy / immunology
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Clonal Anergy / physiology
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DNA-Binding Proteins / analysis*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Forkhead Transcription Factors
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Homeostasis / immunology
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Interleukin-15 / pharmacology
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Interleukin-15 / physiology
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Interleukin-2 / biosynthesis
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Interleukin-2 / genetics
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Interleukin-2 / pharmacology
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Interleukin-6 / pharmacology
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Interleukin-6 / physiology
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Lipopolysaccharides / immunology
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / immunology
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Lymphocyte Activation / physiology*
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Membrane Glycoproteins / pharmacology
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Membrane Glycoproteins / physiology
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Mice
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Mice, Knockout
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Polysaccharides, Bacterial / immunology
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Polysaccharides, Bacterial / pharmacology
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Receptors, Interleukin-2 / analysis*
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Receptors, Interleukin-2 / immunology
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Salmonella enteritidis / immunology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
Substances
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Antigens, CD
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B7-2 Antigen
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CD4 Antigens
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Cd86 protein, mouse
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-15
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Interleukin-2
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Interleukin-6
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Lipopolysaccharides
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Membrane Glycoproteins
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Polysaccharides, Bacterial
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Receptors, Interleukin-2