T lymphocytes are currently thought to play a pivotal part in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Our recent results demonstrate that direct contact between T cells and monocyte-macrophages is a potent pro-inflammatory mechanism that triggers massive up-regulation of the pro-inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-a (TNF) as well as the induction of matrix metalloproteinases (MMPs) in the latter cells. These products have been implicated in both RA and MS pathogenesis. To date cell-cell contact is the only endogenous mechanism described that displays such an activity in monocyte-macrophages. Generally, the latter cells are stimulated in vitro by bacterial products (i.e., lipopolysaccharides, LPS), or non-specific stimuli (i.e., phorbol esters), the activation achieved by soluble cytokines such as IFN-g being poor. Since direct cellular contact occurs at the inflammatory site, we hypothesized that this mechanism is relevant to the pathogenesis of chronic inflammatory disorders. We have shown that this mechanism is modulated by interferon b (IFNb) in a way reflecting the beneficial therapeutic effects of the latter in relapsing-remitting MS patients. We also identified HDL-associated apolipoprotein A-I (apo A-I), i.e., a plasma negative acute-phase protein that proved to be a specific inhibitor of contact-mediated monocyte activation and interacts with the surface activating factor on stimulated T cells.
The overall purpose of our research is to characterize the molecular basis of cell-cell contact whereby stimulated T lymphocytes induce and modulate the activation stage of surrounding effector cells, particularly monocyte-macrophages in the context of chronic and destructive inflammatory diseases. To this end we are investigating the following crucial aspects:
1) Which are the activating factors on stimulated T lymphocytes involved in monocyte activation upon direct cellular contact, i.e., identity, hierarchy, sequence of signals, crosstalk, etc. and which is the apo A-I ligand (apoAI-L)?
2) Which are the counter-ligands on monocytes involved in their activation upon contact with stimulated T lymphocytes? Which is the counter-ligand/receptor of apoAI-L on monocytes?
3) Which transduction pathways and nuclear factors are involved in the induction of cytokines and their inhibitors in monocytes upon activation by apoAI-L? Which pathways regulate the production of IL-1b, TNF-a and IL-1Ra? Are there pathways able to differentially regulate the production of cytokines and their inhibitors, particularly IL-1b and IL-1Ra, and TNF-a and TNF-sRs?
4) How does the stage of monocyte differentiation affect cytokine production? Does contact with stimulated T lymphocytes affect the differentiation of dendritic cells and macrophages?
5) Which T lymphocyte subpopulations possess the ability to preferentially activate monocytes, and which are the triggering factors acting on T lymphocytes for the expression of activating factors (apo AI-L)? Do resting T lymphocytes or T-regulatory cells play a role?
6) What pathways in cellular interaction lead to fibrosis due to the action of chemokines (in collaboration with Dr C. Chizzolini) and the interaction with adipose tissue (in collaboration with Dr C. Meier's group).
7) How does the inhibition by apo A-I of lymphocyte-monocyte contact affect the expression of genes on monocytes, as determined by microarray (in collaboration with Dr S. Ferrari-Lacraz)?8) Whenever possible, the validity of our results is tested by clinical studies (e.g. apo A-I levels in MS and septic patients, cytokines and acute-phase proteins in chronic inflammatory diseases). These studies are undertaken in close collaboration with Dr. P. Roux-Lombard.