title: Sonic hedgehog signaling modulates activation of and cytokine production by human peripheral CD4+ T cells.
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.
authors.affiliation: Immunobiology Group, Medical Research Council Center for Inflammation Research, University of Edinburgh School of Medicine, Teviot Place, Edinburgh EH8 9AG, Scotland, United Kingdom.
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Stewart
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Lowrey
authors.forename: Sonia J
authors.initials: SJ
authors.lastname: Wakelin
authors.forename: Paul M
authors.initials: PM
authors.lastname: Fitch
authors.forename: Susannah
authors.initials: S
authors.lastname: Lindey
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Dallman
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lamb
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Howie
mesh_terms: D000276:Adjuvants, Immunologic / Q000097:blood / Q000502:physiology; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D004306:Dose-Response Relationship, Immunologic; D053823:Hedgehog Proteins; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000097:blood / Q000502:physiology; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000097:blood / Q000276:immunology / Q000502:physiology*; D000099192:CD69 Antigens
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D053823:Hedgehog Proteins; D007106:Immune Sera; D007371:Interferon-gamma; D007376:Interleukin-2; D037181:Lectins, C-Type; D008565:Membrane Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D015534:Trans-Activators; D000099192:CD69 Antigens; C509239:SHH protein, human