Sonic Hedgehog Promotes Cell Cycle Progression in Activated Peripheral CD4+ T Lymphocytes1

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-G2 proliferative phase of the cell cycle. Neutralizing anti-Shh Ab reduced T cell proliferation by inhibiting cell transition into the S-G2 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.