Abstract
Sonic hedgehog (Shh) is important in the growth and differentiation of a variety of cell types, including the development of T cells in the thymus. This prompted us to investigate whether Shh signaling is a functional component of the physiological response of human mature CD4(+) T cells following Ag recognition. In this study, we demonstrate that Shh and its receptor Patched (Ptc) are expressed on resting and activated human peripheral CD4(+) T cells. In approximately one-half of the randomly selected, anonymous blood donors tested, exposure of anti-CD3/28 Ab-activated CD4(+) T cells to the biologically active N-terminal Shh peptide increased the transcription of ptc, thereby demonstrating that Shh signaling had occurred. Furthermore, the addition of exogenous Shh amplified the production of IL-2, IFN-gamma, and IL-10 by activated CD4(+) T cells. The synthesis of IL-2 and IFN-gamma, but not IL-10, by CD4(+) T cells was down-regulated by the addition of neutralizing anti-Shh Ab. Cell surface expression of CD25 and CD69 on activated T cells was up-regulated by exogenous Shh, whereas in the presence of the neutralizing anti-Shh Ab expression it was reduced. Collectively, our findings demonstrate that Shh-mediated signaling is a physiological component of T cell responses, which acts to modulate CD4(+) T cell effector function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / blood
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Adjuvants, Immunologic / physiology
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Antigens, CD / biosynthesis
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism*
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Cells, Cultured
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis*
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Cytokines / blood
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Dose-Response Relationship, Immunologic
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Hedgehog Proteins
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Humans
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Immune Sera / pharmacology
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Lectins, C-Type
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Lymphocyte Activation / immunology*
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Membrane Proteins / blood
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Membrane Proteins / physiology
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Patched Receptors
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Receptors, Cell Surface
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Interleukin-2 / metabolism
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Signal Transduction / immunology*
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Trans-Activators / blood
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Trans-Activators / immunology
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Trans-Activators / physiology*
Substances
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Adjuvants, Immunologic
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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Cytokines
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Hedgehog Proteins
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Immune Sera
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Interleukin-2
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Lectins, C-Type
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Membrane Proteins
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Patched Receptors
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Receptors, Cell Surface
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Receptors, Interleukin-2
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SHH protein, human
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Trans-Activators
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Interferon-gamma