Abstract
Foxp3(+) regulatory T (Treg) cells include thymic-derived natural Treg and conventional T-derived adaptive Treg cells. Both are proposed to play important roles in downregulating inflammatory immune responses. However, the mechanisms of Treg expansion in inflammatory environments remain unclear. In this study, we report that, in an autoimmune-like graft-versus-host disease model of DBA/2 (H-2(d)) donor to BALB/c (H-2(d)) recipients, donor Treg cells in the recipients predominantly originated from expansion of natural Treg cells and few originated from adaptive Treg cells. In vivo neutralization of IFN-γ resulted in a marked reduction of donor natural Treg expansion and exacerbation of graft-versus-host disease, which was associated with downregulation of host APC expression of B7H1. Furthermore, host APC expression of B7H1 was shown to augment donor Treg survival and expansion. Finally, donor Treg interactions with host APCs via B7.1/B7H1 but not PD-1/B7H1 were demonstrated to be critical in augmenting donor Treg survival and expansion. These studies have revealed a new immune regulation loop consisting of T cell-derived IFN-γ, B7H1 expression by APCs, and B7.1 expression by Treg cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / metabolism
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Antigen-Presenting Cells / pathology
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Antigens, Surface / biosynthesis
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Antigens, Surface / physiology*
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / physiology*
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / pathology
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B7-1 Antigen / biosynthesis
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B7-1 Antigen / physiology*
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B7-H1 Antigen
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Disease Models, Animal
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Graft vs Host Disease / genetics
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Graft vs Host Disease / immunology
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Graft vs Host Disease / pathology
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Immunity, Innate / genetics
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Inducible T-Cell Co-Stimulator Ligand
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / metabolism
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Knockout
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Peptides / antagonists & inhibitors
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Peptides / physiology*
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Programmed Cell Death 1 Receptor
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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T-Lymphocytes, Regulatory / pathology
Substances
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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Cd274 protein, mouse
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Inducible T-Cell Co-Stimulator Ligand
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Peptides
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Programmed Cell Death 1 Receptor
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Interferon-gamma