Regulation of B-1 lymphocyte trafficking through the C5a/C5aR1 axis

In the past years the knowledge about the complement system increased significantly. Surprising discoveries and clinical breakthroughs pushed the boundaries of classical “text book”-knowledge of the complement system. Classically, it was thought that the main source of complement is within the circulation; nowadays local cellular complement sources are getting more attention. Therefore, previously unappreciated functions of complement are gaining more importance. In this proposal we want to delineate the cell-regulatory functions of C5a within the immune cell network and define the mechanisms underlying such functions with a specific focus on B-1 B lymphocytes. B-1 B lymphocytes mediate broad and constitutive antibody-based immune responses against several types of infections. Preliminary and published data generated in my group show important novel roles for the receptor for the complement component C5a, the C5a receptor 1 (C5aR1), in B-1 lymphocyte biology. We showed for the first time C5aR1 expression on B-1 lymphocytes and that the lack of this receptor has functional consequences for the B-1 lymphocyte biology on several levels. Under homeostatic conditions, C5aR1-deficient mice show less B-1 lymphocytes in their main compartment, the peritoneal cavity (PeC), mainly due to decreased levels of CXCL13. In vitro experiments revealed that this is most likely due to a disturbance of a newly discovered pathway in which C5aR1 drives, together with TLR2 and IL-10R, CXCL13 production in peritoneal macrophages. At the same time C5aR1-/- mice show increased numbers of B-1 lymphocytes in the spleen, which is accompanied with elevated amounts of individual immunoglobulin (Ig) M specificities known as natural (n) IgM antibodies. Since they are constitutively produced, nIgM and B-1 lymphocytes are considered as an important part of innate immunity that, together with the complement system, act as first line of defense against infectious agents. Moreover, nIgM performs essential housekeeping functions by mediating the clearance of apoptotic cells, misfolded proteins and autoantigens generated under oxidative stress or due to protein modification in the course of metabolic processes. Under inflammatory conditions C5aR1 seems to be necessary for B-1 lymphocyte migration to remote tissues like the spleen, a topic not yet adequately addressed in current publications. In this project, we aim to define the role of C5aR1 in the development, function and migration of individual B-1 lymphocyte subsets. Moreover, we will determine, how the C5a/C5aR1 axis regulates B-1 lymphocyte nIgM production and whether it modulates B-1 lymphocyte functions by tuning BCR activity. Finally, we will test the biological relevance of our findings in B-1 lymphocyte-dependent animal models of human diseases.