T lymphocyte recruitment in Helicobacter pylori-associated diseases

Sammanfattning: Helicobacter pylori (Hp) infection is associated with pronounced infiltration of granulocytes and lymphocytes into the gastric mucosa, resulting in active chronic gastritis that may develop into duodenal ulcer disease or gastric adenocarcinoma (GC). Infiltrating T cells play a major role in the pathology of these diseases, but the signals involved in recruitment of T cells from blood to H. pylori-infected tumour-free and tumour tissues are not well understood. In addition, CD4+CD25high regulatory T cells (Treg) may limit effector responses of infiltrating T cells, thereby affecting immunity to both Hp infection and GC. The overall aim of this thesis was to investigate the mechanisms of Hp-induced T cell transendothelial migration (TEM) in healthy volunteers and Hp-infected GC patients. We wanted to determine the homing mechanisms used by both ordinary mucosal T cells and Treg in both Hp-induced gastritis and tumour mucosa, and to investigate the potential suppressive function of mucosal Treg in Hp infection and in GC.In the transwell system, employing a monolayer of human umbilical vein endothelial cells to mimick TEM, H. pylori induced recruitment of activated memory CD4+ and CD8+ T cells with a Th1 phenotype. Both live H. pylori as well as secreted components, such as urease, induced T cell recruitment. H. pylori-induced T cell TEM was dependent on LFA-1-ICAM-1 interactions and H. pylori readily up-regulated ICAM-1 on the endothelium, as well as increased the production of T cell recruiting chemokines during TEM. However, in Hp-infected individuals and in GC patients T cell TEM towards H. pylori was dramatically decreased. There was a corresponding decrease in attachment of T cells to the endothelial monolayer during TEM and also a decreased production of the T cell recruiting chemokines IP-10, MDC and RANTES. Furthermore, we could also detect increased frequencies of Treg in blood from the GC patients compared to healthy individuals, suggesting that these cells might play a role in the decreased T cell TEM. Indeed, depletion of Treg from blood lymphocytes increased T cell TEM towards H. pylori in GC patients, but not in healthy volunteers. When investigating the homing receptors on T cells present in the tumor-free and tumour mucosa of GC patients, we found that there were decreased frequencies of T cells expressing the typical mucosal homing receptor alpha4beta7 and increased frequencies of T cells expressing the lymph node homing receptor L-selectin. This was probably caused by decreased levels of MAdCAM-1+ blood vessels and increased levels of PNAd+ blood vessels in the tumour, suggesting that endothelial cells within tumours arising at mucosal sites do not support extravasation of typical mucosa-infiltrating T cells. Furthermore, investigation of mucosal Treg function revealed that these cells were increased in frequency in the tumour compared to tumour-free mucosa and that they were able to suppress H. pylori-specific T cell responses in both tissue types. Furthermore, Treg expressed high levels of L-selectin and chemokine receptor CCR4, suggesting that these molecules are involved in recruitment of Treg to both tissue types. Our results suggest that live H. pylori and its secreted products contribute to T cell recruitment to the gastric mucosa and that the presence of Treg in blood or mucosa of GC patients may hamper anti-tumour immunity by reducing T cell TEM and by suppressing H. pylori-induced T cells responses in the tumour mucosa.