Abstract
FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / administration & dosage
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Antibodies / pharmacology
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Bone Marrow Transplantation*
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CD8-Positive T-Lymphocytes / cytology*
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cell Proliferation / drug effects
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Dendritic Cells / cytology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology
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Epitopes / immunology
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Female
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Forkhead Transcription Factors / metabolism*
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Graft vs Host Disease / immunology
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Graft vs Host Disease / pathology
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Immune Tolerance / drug effects
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Immune Tolerance / immunology*
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Interleukin-2 / immunology
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Lymph Nodes / drug effects
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Mice
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Mice, Inbred C57BL
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Phenotype
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Sirolimus / administration & dosage
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Sirolimus / pharmacology
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Survival Analysis
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T-Lymphocytes, Regulatory / cytology*
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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Transforming Growth Factor beta / pharmacology
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Transplantation, Homologous
Substances
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Antibodies
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Epitopes
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2
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Transforming Growth Factor beta
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Sirolimus