Abstract
We used a model of combined bone marrow and heart transplantation, in which tolerance and stable chimerism is induced after conditioning with fractionated irradiation of the lymphoid tissues and anti-T-cell antibodies. Graft acceptance and chimerism required host CD4(+)CD25(+) Treg production of IL-10 that was in-turn enhanced by host invariant natural killer (NK) T-cell production of IL-4. Up-regulation of PD-1 on host Tregs, CD4(+)CD25(-) conventional T (Tcon) cells, and CD8(+) T cells was also enhanced by NKT cell production of IL-4. Up-regulated PD-1 expression on Tregs was linked to IL-10 secretion, on CD8(+) T cells was linked to Tim-3 expression, and on CD4(+) Tcon cells was associated with reduced IFNγ secretion. Changes in the expression of PD-1 were induced by the conditioning regimen, and declined after bone marrow transplantation. In conclusion, NKT cells in this model promoted changes in expression of negative costimulatory receptors and anti-inflammatory cytokines by Tregs and other T-cell subsets in an IL-4-dependent manner that resulted in tolerance to the bone marrow and organ grafts.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, Differentiation / immunology
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Antigens, Differentiation / metabolism
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Antilymphocyte Serum / pharmacology
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Bone Marrow Transplantation / immunology*
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Communication / immunology
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Cells, Cultured
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Female
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Fluorescent Antibody Technique
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Heart Transplantation / immunology*
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Hepatitis A Virus Cellular Receptor 2
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Immune Tolerance / immunology*
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-10 / genetics
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Interleukin-10 / immunology
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Interleukin-10 / metabolism
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Interleukin-4 / genetics
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Interleukin-4 / immunology
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Interleukin-4 / metabolism
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Male
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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, Knockout
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Natural Killer T-Cells / immunology*
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Natural Killer T-Cells / metabolism
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Programmed Cell Death 1 Receptor
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Receptors, Virus / immunology
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Receptors, Virus / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Transplantation Conditioning / methods
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Up-Regulation / drug effects
Substances
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Antigens, Differentiation
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Antilymphocyte Serum
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Havcr2 protein, mouse
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Hepatitis A Virus Cellular Receptor 2
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Receptors, Virus
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Interleukin-10
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Interleukin-4
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Interferon-gamma