The function of leucocyte-specific tetraspanins CD53 and CD37 in the immune system – regulators of leucocyte migration

Leucocyte migration is central to the generation of effective immunity. Notably, dendritic cells (DCs) must migrate from the periphery to the lymph nodes (LNs) to present pathogen-derived antigen to naïve T cells, which themselves must recirculate between lymph nodes to increase the chance of recognition of their cognate antigen. Molecules and cellular components that regulate leucocyte trafficking are therefore essential to allow efficient migration to occur. For example, L-selectin and integrins are important adhesion molecules and cytoskeletal rearrangement is important for dynamic changes in cell morphology during migration. Another type of molecule well known to regulate migration and adhesion in non-immune cells are the tetraspanins: a family of integral membrane proteins, known to be important organisers of the cell membrane. This project uses reverse genetics and in vivo models to determine the function of the two uniquely leucocyte-expressed tetraspanins CD37 and CD53, and reveals that these tetraspanins have a common role in regulating the migratory capability of leucocytes. The first study of the immunophenotype of the novel CD53^-/- mouse is presented, showing compelling evidence for an unprecedented function of tetraspanin CD53 in the regulation of L-selectin, through a metalloproteinase-dependent mechanism, and thus this tetraspanin has roles in lymphocyte homing and inflammation. Further work on the CD37^-/- mouse illustrates a function for CD37 in promoting DC migration from the periphery to the LNs, mediated through regulation of cytoskeletal rearrangement by Rho GTPases. Thus, I can now demonstrate that tetraspanins not only regulate non-immune cell migration, but also leucocyte migration. Leucocyte-specific tetraspanins, CD37 and CD53 can mediate DC migration from the periphery to LNs and naïve lymphocyte recirculation, respectively.