Functional role of Srec-I on regulatory T cells

The human organism must react on a broad range of exogenous and endogenous danger signals in order to mount an appropriate immune response. Pattern recognition receptors (PRRs) thereby play a critical role in delivering stimulatory or inhibitory signals to immune cells. The importance of tight regulation of such processes becomes obvious considering the broad range of immunological disorders like rheumatoid arthritis or systemic lupus erythematosus. Over the past years regulatory T cells (T-regs) have been recognized as one of the key elements in controlling immune responses. We have recently identified a novel receptor on human T-regs. Scavenger receptor on endothelial cells I (Srec-I) was characterized, using a retroviral expression cloning approach. Srec-I binds oxidized low-density lipoprotein (oxLDL), an endogenous danger signal. Since only a portion of CD4 + CD25 + T cells expresses this cell surface receptor, Srec-I could be a novel subpopulation marker on regulatory T cells. Most importantly engagement of Srec-I with our monoclonal antibody (mAb) 2-98 enhanced the inhibitory function of regulatory T cells significantly. Such a functional effect has so far not been described for other surface molecules on regulatory T cells. In this project we want to investigate if sensing of endogenous danger signals (oxLDL) by Srec-I is involved in boosting the function of T-regs in contrast to pathogen-derived signals induced via TLRs. Analyzing the molecular and functional consequences of Srec-I engagement on regulatory T cells offers the opportunity to get new insights into the molecular mechanisms of how T-regs suppress immune responses. In addition, we will examine if Srec-I might be a suitable and informative marker to define a special subpopulation within CD4 + CD25 + T-regs in human diseases.

Inflammation is the incitement that turns on adaptive immune responses. The endogenous mechanisms, which regulate and terminate inflammatory reactions and consequently turn off immune reactions, are incompletely understood. Natural regulatory T cells (Tregs) play an essential role in the control of adaptive immune responses. The results obtained within this project demonstrate that the cell surface receptor Scavenger receptor on endothelial cells I (Srec-I) is a novel regulator of the suppressive function of human Tregs. We have discovered herein that interactions between Srec-I from antigen presenting cells, e.g. dendritic cells (DCs) and Srec-I on Tregs down- regulate the suppressive function of Tregs. In contrast, blocking of this interaction with monoclonal antibodies (mAbs) against Srec-I interferes with this regulatory pathway leading to an enhanced inhibitory capacity of natural Tregs. Yet, Srec-I is not a specific marker for natural Tregs but has to be considered to be a general activation marker that can be also expressed on conventional T cells upon appropriate activation. Srec-I is a receptor for oxidized LDL (oxLDL). OxLDL and its major component oxidized phospholipids (ox-Pls) are side-products of collateral damage of surrounding tissue caused by free oxygen radicals in inflammatory processes and classical indicators for inflammation. Thus, ox-Pls are produced naturally in our body and represent endogenous danger signals for the immune system. The results obtained in this project demonstrate, however, that ox-Pls selectively regulate the functional repertoire of human T cells. Ox-Pls were found to prevent the development of inflammatory, so called Th1-type T cell responses, T cell proliferation and both the induction of as well as the effector-phase of cytotoxic T cells (CTL) induced through stimulation via the TCR/CD3-complex. These observations suggest that direct inhibitory effects of ox-Pls on T cells might contribute to control T cell function and to avoid overwhelming or even detrimental immune responses at sites of inflammation. T cells have been implicated in mediating many aspects of autoimmune inflammation. Thus, ox-Pls might be suitable tools to control undesired T cell responses in autoimmune diseases including rheumatoid arthritis or systemic lupus erythematosus like other prominent immunosuppressive drugs such as cyclosporine A, glucocorticoids or rapamycin. Taken together, ox-Pls and Srec-I are novel modulators of adaptive immunity with unique immunosuppressive characteristics identified in this project.