Sonic hedgehog promotes cell cycle progression in activated peripheral CD4(+) T lymphocytes.
Sonic hedgehog (Shh) signaling is important in the growth and differentiation of many cell types and recently has been reported to play a role in T cell development in the thymus. This prompted us to investigate whether or not Shh contributes to the clonal expansion of peripheral CD4(+) T cells. In this study, we demonstrate that Shh and other components of the signaling pathway patched, smoothened, and Gli1 (glioma-associated oncogene) are expressed in peripheral CD4(+) T cells. The addition of the biologically active amino-terminal Shh peptide had no effect on resting CD4(+) T cells, but significantly enhanced proliferation of anti-CD3/28 Ab-activated CD4(+) T cells. This was not due to antiapoptotic effects, but by promoting entry of T cells into the S-G(2) proliferative phase of the cell cycle. Neutralizing anti-Shh Ab reduced T cell proliferation by inhibiting cell transition into the S-G(2) phase, suggesting that endogenously produced Shh plays a physiological role in the clonal expansion of T cells. Furthermore, we have observed a significant up-regulation of Shh and Gli1 (glioma-associated oncogene) mRNA in activated CD4(+) T cells with or without addition of exogenous Shh, which corresponds with maximal CD4(+) T cell proliferation, whereas bcl-2 was only up-regulated in activated cells in the presence of Shh. Our findings suggest that endogenously produced Shh may play a role in sustaining normal CD4(+) T cell proliferation and exogenously added Shh enhances this response.
Lowrey
Jacqueline A
JA
Immunobiology Group, Medical Research Council Center for Inflammation Research, University of Edinburgh Medical School, Edinburgh, United Kingdom. J.A.Lowrey@ed.ac.uk
Stewart
Gareth A
GA
Lindey
Susannah
S
Hoyne
Gerard F
GF
Dallman
Margaret J
MJ
Howie
Sarah E M
SE
Lamb
Jonathan R
JR
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002453:Cell Cycle / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D019254:Genes, bcl-2; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology; D000072079:Patched Receptors; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D010446:Peptide Fragments; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1