Analysis of the Role of Membrane-bound Matrix Metalloproteinases in Dendritic Cell Biology

Dendritic cells (DC) represent a distinct population of leukocytes with the unique capacity to initiate primary immune responses. Their ability to penetrate basement membranes and intervening extracellular matrix (ECM)-rich connective tissues and to migrate to T cell rich areas seems to be a prerequisite for the induction of primary immune responses. Although the area of DC is currently under intensive investigation the underlying mechanisms of DC migration are only incompletely understood. Matrix metalloproteinases (MMPs) comprise a family of zinc-containing endopeptidases with a wide substrate variety including all components of the ECM. Membrane-type matrix metalloproteinases (MT-MMPs), a subgroup of MMPs, are transmembrane proteins, which have been shown to be involved in tumor cell invasion. In terms of migration DC might share functional characteristics with invasive tumor cells. Thus, MT-MMPs might represent important mediators of pericellular proteolysis enabling DC precursors to migrate from the blood to their target tissues and/ or mediating migration of DC from peripheral tissues to regional lymph nodes. This project aims to identify MT-MMPs that play a role in DC development and function and to determine how they participate in DC migration. Initially we will focus on MT1-MMP because preliminary data indicates a role for MT1-MMP in DC biology. We will use a MT1-MMP deficient mouse model, which will allow to study DC subtypes (including epidermal Langerhans cells), their migratory function, and the interaction of DC with T cells in vivo and in vitro. Furthermore it is planned to extend in vitro studies to human cells in order to test the generality of the results obtained from the murine system. The availability of the methodologies to propagate and to study DC in vitro and the increasing availability of mouse mutants deficient in MMPs, should allow elucidation of the roles that MMP s play in DC biology.