Lymphocyte recirculation through the body is not a random process, but lymphocytes migrate through selected tissues depending on their activation and maturation stage, subtype, and tissue of origin. This tissue-specific migration is dependent on selected adhesion molecules on lymphocytes as well as endothelial cells, and production of tissue-specific chemokines and expression of their respective receptors on circulating lymphocytes. The aim of the project is to characterize the mechanisms of lymphocyte recruitment to mucosal tissues, both during steady state, in Helicobacter pylori induced gastric inflammation, and in gastrointestinal tumors. We use tissue material from gastric cancer patients and healthy and H. pylori infected volunteers, as well as circulating blood lymphocytes from immunized subjects. We have also established an in vitro system to examine transendothelial migration of lymphocytes. More specifically, we are studying the expression of endothelial adhesion molecules and chemokines in inflamed and tumor tissues, and also the ability of tumor cells to directly influence the expression of endothelial adhesion molecules used for recruitment of efficient effector cells. In addition to this, we have recently identified a substantial decrease in expression of the chemokine decoy receptor D6 in colon cancer. In healthy tissues, D6 mediates endocytosis and destruction of surplus chemokines, but in tumors this ability is abrogated, probably leading to increased recruitment of tumor associated macrophages and Treg. Finally, the ability of regulatory T cells to influence lymphocyte recruitment in cancer patients and after immunization is investigated. Using a mouse model of spontaneous colon cancer and in vivo microscopy, we will also extend these studies to in vivo monitoring of the effect of Treg on lymphocyte extravasation into tumors. The knowledge gained from these studies will be used to improve current strategies for mucosal immunization and immunotherapy against mucosal tumors.
Important publications:Enarsson K., Innocenti M., Backert S, and Quiding-Järbrink M. (2005) Helicobacter pylori induce transendothelial migration of activated memory T cells. Infect. Immun. 73: 761-9.
Enarsson K., Lundgren A., Hermansson M., Svennerholm A.-M., Lundin B. S., and Quiding-Järbrink M. (2006) Function and recruitment of mucosal regulatory T cells in human chronic H. pylori-infection and gastric adenocarcinoma. Clin. Immunol. 121: 358-368.
Enarsson K., Lundin S., Johnsson E., Brezicka T., and Quiding-Järbrink M. (2007) CD4+CD25high regulatory T cells reduce transendothelial migration of T cells from cancer patients. Eur. J. Immunol. 37: 282-291.
Hansson M., Hermansson M., Svensson H., Elfvin A., Hansson L.-E., Johnsson E., Sjöling Å., Quiding-Järbrink M. (2008) CCL28 is increased in human Helicobacter pylori-induced gastritis and mediates recruitment of gastric immunoglobulin A-secreting cells. Infect. Immun. 76: 3304-3311.
Sundström, P., Lundin B. S., Nilsson L.-Å., and Quiding-Järbrink M. (2008) Human IgA-secreting cells induced by intestinal, but not systemic, immunization respond to TECK (CCL25) and MEC (CCL28). Eur. J. Immunol. 38: 3327-3338.
Svensson H., Hansson M., Kilhamn J., Backert S., and Quiding-Järbrink M. (2009) Selective upregulation of endothelial E-selectin in response to Helicobacter pylori-induced gastritis. Infect. Immun. 77: 3109-16.