Function of co-stimulatory pathways in atheroslerosis

• Applicant: Professorin Dr. Esther Lutgens
• Subject Area: Cardiology, Angiology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 29385330

The immune system plays a decisive role in the development and progression of atherosclerotic plaques. Key players in modulating immune responses are co-stimulatory and co-inhibitory molecules that direct the phenotypes of T cells, dendritic cells (DC) and macrophages towards an effector (pro-inflammatory) or regulatory (anti-inflammatory) profile, and regulate the expression of adhesion molecules, cytokines, chemokines and their receptors. Co-stimulatory molecules act at the immunological synapse , i.e. where the T cell receptor interacts with the major histocompatibility complex (MHC) on antigen-presenting cells (APC), such as B cells, DC, macrophages. Some co-stimulatory molecules can also generate more peripheral immunological responses on endothelial cells, smooth muscle cells (SMC), and platelets. In atherosclerosis, inhibition of the co-stimulatory CD40-CD154 (CD40 ligand)-dyad markedly reduces atherosclerosis. However, whether inhibition of CD154 or CD40 is athero-protective depends on the cell types and CD40-TRAF (Tumor Necrosis Factor Receptor Associated Factor) signaling pathways involved. In addition, inhibition of CD40-CD154 interactions not only changes the local immunological milieu of the plaque, but also affects the systemic immune system by converting T cells, DC and macrophages into effector or regulatory immune cells. The CD40-CD154 system is a unique dyad, as it is not strictly a mediator of T cell activation, but mainly functions to activate APC. Depending on the pathology, APC express a plethora of co-stimulatory molecules, which in turn activate T cells and determine the phenotype of the T cell and the APC. This suggests that the reduction in atherosclerosis and the stable plaque phenotype due to inhibition of CD154/CD40 may be mediated via actions of other co-stimulatory dyads, function of which may be influences by CD40/CD154-dependent signaling. We hypothesize that the CD40-CD154 system exerts its actions via other co-stimulatory receptor-ligand dyads like CTLA-4-B7.1/2, GITR-GITRL, and CD27-CD70, and that this occurs in a cell-type specific fashion, through up-regulation of chemokine and chemokine receptors, and via cell-type specific signal transduction cascades. In this proposal we will investigate the cell-type specific role of CTLA-4, GITR, CD27, and CD70 in atherosclerosis, as well as their effects on the immune system by using ‘gain and loss of function’ animal models. Moreover, we will unravel the effects of these co-stimulatory receptor-ligand dyads on chemokine and chemokine receptor expression and function. Finally, we will investigate the direct regulation of the chemokine system by interaction of CD40-CD154 and changes thereof in mice functionally impaired in CD40-CD154 signaling. Collectively, these experiments will reveal the contribution of these novel co-stimulatory molecules and the chemokine system to CD40-dependent atherosclerosis. We hope to develop new therapeutic targets that bear the potential of CD40 inhibition without conferring the harmful side effects associated with such therapy.

• DFG Programme: Research Units
• Subproject of: FOR 809: Chemokines and Adhesion Molecules in Cardiovascular Pathogenesis
• Participating Person: Professor Dr. Norbert Gerdes