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Sonic Hedgehog Signaling Modulates Activation of and Cytokine Production by Human Peripheral CD4⁺ T Cells¹

Gareth A. Stewart^*,, Jacqueline A. Lowrey^*,, Sonia J. Wakelin^*,, Paul M. Fitch^*,, Susannah Lindey^*,, Margaret J. Dallman, Jonathan R. Lamb^*, and Sarah E. M. Howie^2,*,

^* Immunobiology Group, Medical Research Council Center for Inflammation Research, Respiratory Medicine Unit, and Department of Pathology, University of Edinburgh School of Medicine, Edinburgh, United Kingdom; and Department of Biological Sciences, Imperial College of Science, Technology and Medicine, London, United Kingdom

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-, and IL-10 by activated CD4⁺ T cells. The synthesis of IL-2 and IFN-, 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.

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