Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells.
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.
Fehérvári
Zoltán
Z
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Shogo-in 53, Sakyo-ku, Kyoto 606-8507, Japan. zed72@frontier.kyoto-u.ac.jp
Sakaguchi
Shimon
S
D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology / Q000502:physiology; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D015704:CD4 Antigens / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology / Q000502:physiology; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors; D006706:Homeostasis / Q000276:immunology; D019409:Interleukin-15 / Q000494:pharmacology / Q000502:physiology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology / Q000502:physiology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011135:Polysaccharides, Bacterial / Q000276:immunology / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000276:immunology; D012477:Salmonella enteritidis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
D015703:Antigens, CD; D051940:B7-2 Antigen; D015704:CD4 Antigens; C497965:Cd86 protein, mouse; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019409:Interleukin-15; D007376:Interleukin-2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011135:Polysaccharides, Bacterial; D015375:Receptors, Interleukin-2