Research Report 2010 - MDC

Structure of the GroupGroup LeaderPD Dr. Uta E. HöpkenKristina SchradiSusann WinterUta E. Höpken(Delbrück Fellow)Graduate StudentsAngela MensenKatharina WichnerTechnical AssistantsKatrin RäbelHeike SchwedeRegulatory Mechanisms of LymphocyteTrafficking in Homeostasis andImmunopathogenesisRegulated lymphocytic recirculation is pivotal in immune system homeostasis andimmunopathogenesis. Our work is focused on the role of the chemokine/chemokinereceptor system in homeostatic lymphocytic recirculation, systemic and mucosal immuneresponses, and lymphoid neo-organogenesis during chronic inflammatory or infectiousdiseases. We further focus on the molecular mechanisms of immune surveillance inpreclinical mouse models for B cell lymphoma.Lymphocytic homeostasis and mucosal immunityChemokine receptors regulate peripheral homeostaticlymphocyte recirculation and mucosal immunityRecently, we showed that the chemokine receptor CCR7controls not only lymphocyte trafficking to and withinsecondary lymphoid organs, but also homeostaticmigration of T and B lymphocytes through non-lymphoidperipheral tissues. CCR7 deficiency results in massiveaccumulation of T- and B-lymphocytes in the peritonealcavity. Mechanistically, an increase in peritoneallymphocyte numbers is caused by impaired egress ofCCR7-deficient lymphocytes from body cavities. Mostinterestingly, disturbed peripheral recirculation of lymphocytesalso resulted in the development of ectopiclymphoid-like follicles and age-dependent histopathologicalchanges in the gastrointestinal tract of CCR7-deficient mice. Since the formation of ectopic folliclesprecedes the development of epithelial histomorphologicalchanges, we suggest that crosstalk betweenlymphoid aggregates and their adjacent epithelial tissuemight contribute to the development of hypertrophicgastropathy.The underlying molecular mechanisms have beenaddressed by performing expression profiling of differentiallyexpressed genes between wild-type epithelialtissue and CCR7 -/- epithelial tissue or mucosal lymphoidaggregates. Several transcription factors and signalingmolecules were selected on basis of the microarraydata and are further characterized as potential mediatorsinvolved in this celluar crosstalk.Chemokine/chemokine receptor function ininfectious gastrointestinal cancer modelsThere is considerable evidence for the involvement ofhomeostatic chemokines in the formation of tertiarylymphoid tissues during chronic inflammatory processessuch as rheumatoid arthritis and Helicobacter pyloriinducedgastritis. A potential relationship betweenchronic inflammation, establishment of extranodal tertiaryfollicles and lymphoma pathogenesis has beeninferred from gastric MALT lymphomas in humans. Wehave analysed the role of the homeostatic chemokinereceptor CXCR5 in the formation of mucosal tertiarylymphoid tissue after H. pylori infection. CXCR5-deficientmice failed to develop lymphoid aggregates in theglandular stomach and exhibited lower H. pylori-specificserum IgG responses compared to infected wild-typemice. Thus, the development of mucosal tertiary ectopicfollicles during chronic H. pylori infection is stronglydependent on the CXCL13/CXCR5 signaling axis.To date, we study the function of additional chemo -kine/chemokine receptors during the pathogenesis of120 Cancer Research