Sonic Hedgehog Signaling Modulates Activation of and Cytokine Production by Human Peripheral CD4+ T Cells

• Published in: The Journal of immunology (1950) 2002-11, Vol.169 (10), p.5451-5457
• Main Authors: Stewart, Gareth A, Lowrey, Jacqueline A, Wakelin, Sonia J, Fitch, Paul M, Lindey, Susannah, Dallman, Margaret J, Lamb, Jonathan R, Howie, Sarah E. M
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - blood; Adjuvants, Immunologic - physiology; Antigens, CD - biosynthesis; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Antigens, Differentiation, T-Lymphocyte - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Cytokines - blood; Dose-Response Relationship, Immunologic; Hedgehog Proteins; Humans; Immune Sera - pharmacology; Interferon-gamma - antagonists & inhibitors; Interferon-gamma - biosynthesis; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - biosynthesis; Lectins, C-Type; Lymphocyte Activation - immunology; Membrane Proteins - blood; Membrane Proteins - physiology; Patched Receptors; Receptors, Cell Surface; Receptors, Interleukin-2 - biosynthesis; Receptors, Interleukin-2 - metabolism; Signal Transduction - immunology; Trans-Activators - blood; Trans-Activators - immunology; Trans-Activators - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.169.10.5451

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.