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

Abstract

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.

Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID–ß2m–/– repopulating cells.

“…[32][33][34] Hedgehog family proteins have also been shown to function in distinct aspects of embryogenesis, and the tissue distribution of individual members is largely separated or else only partially overlapping. 21,22 Thus, it has been unclear which specific hedgehogs function in the BM microenvironment.…”

“…Recently, evidence for the proliferative effect of hedgehog proteins, which have been examined primarily in the case of the sonic hedgehog protein, has accumulated for a variety of cell types, including T lymphocytes, 32 HSCs, and ectoderm-derived cells such as neural progenitors and keratinocytes. [32][33][34] Hedgehog family proteins have also been shown to function in distinct aspects of embryogenesis, and the tissue distribution of individual members is largely separated or else only partially overlapping.…”

Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions

“…We used distilled water with 0.1% Tween-20 as a rinsing solution. 14 Lymph node was employed as the positive control, since T lymphocytes and germinal center cells are positive for Shh, [15][16][17][18] and smooth muscle as the negative control.…”

Sonic Hedgehog Is Produced by Follicular Dendritic Cells and Protects Germinal Center B Cells from Apoptosis

“…In the thymus, Shh signaling plays an important role regulating thymic cellularity as well as the development of CD4 Ϫ CD8 Ϫ thymocytes (25)(26)(27)(28). In addition, the effector function of peripheral CD4 ϩ T cells is modulated by Shh (29,30). However, no evidence of a role for Hh signaling in B cell differentiation and function has been described.…”