Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4+ T cell proliferation and development of regulatory T cells during Helicobacter pylori infection.

Gastric epithelial cells (GECs) express the class II major histocompatibility complex (MHC) and costimulatory molecules, enabling them to act as antigen-presenting cells (APCs) and affect local T cell responses. During Helicobacter pylori infection, GECs respond by releasing proinflammatory cytokines and by increasing the surface expression of immunologically relevant receptors, including class II MHC. The CD4(+) T cell response during H. pylori infection is skewed toward a Th1 response, but these cells remain hyporesponsive. Activated T cells show decreased proliferation during H. pylori infection, and CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) are present at the site of infection. In this study, we examined the mechanisms surrounding the CD4(+) T cell responses during H. pylori infection and found that transforming growth factor ß (TGF-ß) plays a major role in these responses. GECs produced TGF-ß1 and TGF-ß2 in response to infection. Activated CD4(+) T cells in culture with H. pylori-treated GECs were decreased in proliferation but increased upon neutralization of TGF-ß. Naïve CD4(+) T cell development into Tregs was also enhanced in the presence of GEC-derived TGF-ß. Herein, we demonstrate a role for GEC-produced TGF-ß in the inhibition of CD4(+) T cell responses seen during H. pylori infection.

Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment.

Gastric cancer is associated with chronic inflammation and Helicobacter pylori infection. Th17 cells are CD4(+) T cells associated with infections and inflammation; but their role and mechanism of induction during carcinogenesis is not understood. Gastric myofibroblasts/fibroblasts (GMF) are abundant class II MHC expressing cells that act as novel antigen presenting cells. Here we have demonstrated the accumulation of Th17 in H. pylori-infected human tissues and in the gastric tumor microenvironment. GMF isolated from human gastric cancer and H. pylori infected tissues co-cultured with CD4(+) T cells induced substantially higher levels of Th17 than GMF from normal tissues in an IL-6, TGF-ß, and IL-21 dependent manner. Th17 required interaction with class II MHC on GMF for activation and proliferation. These studies suggest that Th17 are induced during both H. pylori infection and gastric cancer in the inflammatory milieu of gastric stroma and may be an important link between inflammation and carcinogenesis.