Because they are at the interface between tissues and blood, vessels are in constant interaction with the adaptive and innate immune systems. The research projects that we are conducting in team 4 are based on two concepts. The first is that a failure to maintain a perfect homeostasis at the blood/vessel interface is likely to result in pathology. The second is that certain immuno-inflammatory cells might be instrumental to restore physiology. Accordingly, our projects are designed to analyze defective regulation of the homeostasis in pathologic vessel walls and to characterize the various cells of the immunity. By nature, these projects bridge vascular biology and immunology.

Systemic adaptive immune response

Immunomodulation of the T-cell compartment : We have shown that atherosclerosis is associated with perturbations in T lymphocyte repertoires and that the T-cell response impact is time-dependent and is deleterious while B-cell response is protective. Proinflammatory Th1 cells and the non-conventional NKT cells are proatherogenic while IL-10, a Th2 cytokine, is atheroprotective. Currently, we develop immunointervention strategies allowing a fine targeting of certain T cell populations. In particular, we will test the efficacy of the ‘T cell vaccination’ procedure that allows to specifically target certain activated T cell clones.

Immunomodulation of the B-cell compartment : We have shown that the protective B cell response arises from a pre-existing reactivity in healthy individuals which is amplified during pathology. Among the antibody reactivities in atherosclerosis, the anti-oxLDL appears to be critical. We therefore designed a strategy to increase the anti-oxLDL humoral response by targeting the dominant epitopes of these modified self-antigens, the phosphorylcholine (PC). We have shown that anti-PC immunity is atheroprotective. These results are highly promising for a future vaccine since the anti-PC immunity would also confer protection against Gram-positive bacteria, notably virulent pneumococci. We are now testing the inocuity of such vaccinal strategy.

Local adaptive immune response

Graft arteriosclerosis represents a condition during which homeostasis between the immune system with the vascular wall is lost. We first also described that lymphoid neogenesis takes place in the adventitia of grafted arteries and leads to the development of ectopic germinal centers in which B cells produce alloantibodies locally. This led us to propose that lymphoid neogenesis might be a therapeutic target for chronic rejection. We now aim at characterizing the factors that trigger ectopic germinal center formation and at determining their function by blocking their formation. Of note, the formation of ectopic germinal centers is not restricted to allografts but can be found in tissues subjected to chronic inflammation such as the adventitia of atherosclerotic arteries.

Innate immune response

The many biological activities achieved by macrophages make them central in the constitution of atherosclerotic plaques. Until recently, the biology of this cell type was thought to be monomorphic, that is, mostly bestowed with inflammatory and oxidative capacities. This view changed when macrophages endowed not with inflammatory but rather reparative abilities were obtained. These so-called M2 or alternatively activated macrophages could be instrumental to treat or prevent atherosclerosis since they may dampen vascular inflammation whilst promoting the stabilisation of the fibrous cap. We are analyzing M1 (inflammatory) and M2 (alternative) macrophages, the stability over time of their phenotype and their functionnal impact on vascular cells.

Molecular regulator of the homeostasis of the vascular interface

We hypothesize that CD31 is a key immunoregulatory molecule able to maintain homeostasis of the leukocyte and vascular compartments because i) CD31 is exclusively and constitutively expressed by blood cells (except erythrocytes) and by endothelial cells; ii) CD31 can establish homophilic binding; iii) CD31 drives a “leave me alone” signal between interacting cells and inhibits cell activation; iv) CD31 expression is altered on certain leukocytes with ageing and proportionally with the extent of atherothrombotic events; v) shedding of CD31 is responsible for the loss of its immunoregulatory ability which however can be rescued; vi) CD31 is a key modulator of the regulatory T cell compartment. We are deciphering whether leukocyte CD31 shedding is increased in coronary artery disease and whether plasma levels of the shed portion of CD31 is a diagnostic/prognostic marker in coronary artery diseases. We also study the mechanisms by which CD31 modulates the regulatory T cell network. Finally we assess the therapeutic potential of CD31 targeting in experimental atherothrombosis.