Abstract
In previous studies, we have shown that murine CD4+CD25+ regulatory T cells produce high levels of TGF-beta1 in a cell surface and/or secreted form, and blockade of such TGF-beta1 by anti-TGF-beta curtails the ability of these cells to suppress CD25- T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-beta1 in suppression by CD4+CD25+ T cells, we show in this study that another TGF-beta1-blocking molecule, recombinant latency-associated peptide of TGF-beta1 (rLAP), also reverses suppression by mouse CD4+CD25+ T cells as well as their human counterparts, CD4+CD25(high) T cells. In addition, we show that CD25- T cells exposed to CD4+CD25+ T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF-beta-inducible surface integrin. In further studies, we show that while CD4+CD25+ T cells from TGF-beta1-deficient mice can suppress CD25- T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4+LAP+, but not CD4+LAP- T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-beta1 produced by CD4+CD25+ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.
MeSH terms
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Adoptive Transfer
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Animals
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / transplantation
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Cell Membrane / metabolism
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Cells, Cultured
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Colitis / genetics
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Colitis / immunology
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Down-Regulation / immunology
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Female
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Humans
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology
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Intestinal Mucosa / immunology
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Intestinal Mucosa / pathology
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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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Mice, SCID
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Peptide Fragments / biosynthesis
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Peptide Fragments / pharmacology
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Protein Binding / immunology
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Protein Precursors / biosynthesis
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Protein Precursors / pharmacology
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Receptors, Interleukin-2 / biosynthesis*
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Receptors, Transforming Growth Factor beta / physiology
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Recombinant Proteins / pharmacology
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Signal Transduction / immunology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / transplantation
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T-Lymphocytes, Regulatory / immunology
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Transforming Growth Factor beta / biosynthesis
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Transforming Growth Factor beta / deficiency
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
Substances
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Inflammation Mediators
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Peptide Fragments
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Protein Precursors
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Receptors, Interleukin-2
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Receptors, Transforming Growth Factor beta
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Recombinant Proteins
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TGFB1 protein, human
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Tgfb1 protein, mouse
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Transforming Growth Factor beta
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Transforming Growth Factor beta1