PI Gerdes

Immunpathogenese 2 - T-Zell-Subpopulationen in der Atherosklerose

Immunpathogenesis 2 - T-Cell Subpopulations in Atherosclerosis

 

Research Interests (background)

Atherosclerosis, the principal cause of most cardiovascular disease, is characterized by a chronic inflammatory reaction within the vessel wall provoked by insufficient clearance of lipid particles.  Although innate immune cells such as monocytes, mast cells, or granulocytes are considered the main effector cells within the plaque, increasing evidence points to a decisive involvement of the adaptive immunity in the pathological processes underlying atherosclerosis. In particular, understanding T lymphocytes and their intricate mechanisms of regulation may foster the perspective that such pathways could be utilized for future therapeutic purposes.

 

Highlights of 2012/2013:

Regulatory T cells can limit potentially harmful reactions of the conventional effector T cell population. In atherosclerosis, the role of this T cell subpopulation which is characterized by the expression of the transcription factor forkhead box protein 3 (Foxp3) has not directly been described. Earlier studies indirectly suggested that regulatory T cells (Tregs) ameliorate atherosclerosis, but exactly how they operate remained unclear. Using a genetically modified mouse model for selective depletion of these anti-inflammatory cells we aimed to determine the causality and the mechanism of action of Treg in atherogenesis. To define the role of Foxp3-expressing Tregs in atherosclerosis, we used the DEpletion of REGulatory T cells (DEREG) mouse, which expresses the human diphtheria toxin (DT) receptor and enhanced green fluorescent protein (eGFP) under control of the Treg-specific Foxp3 promoter, allowing for specific depletion and tracking of Foxp3+ Tregs. Indeed, DT-mediated depletion of Tregs led to doubling of atherosclerotic lesion size and a profound increase in circulating cholesterol concentration, mainly in the very low density lipoprotein (VLDL) fraction. We could further demonstrate that expression of a receptor important in the uptake of cholesterol-rich lipoproteins, sortilin-1, was decreased in the liver and is likely responsible for decreased clearance of pro-atherogenic particles leading to elevated blood cholesterol levels and enhanced atherosclerosis. (Klingenberg & Gerdes et al, JCI, 2013)

 

In another study were able to clarify the role another specialized T cell population in obesity, a frequent co-morbidity of cardiovascular disease. Obesity promotes a chronic inflammatory condition in adipose tissue (AT) and impairment of insulin sensitivity coincides with infiltration of T cells into AT in early stages of obesity. We examined the role of invariant natural killer T (iNKT) cells, a subtype of T cells activated by lipid antigens, on glucose and lipid metabolism in obesity. (Strodthoff et al, ATVB, 2013) When studying these cells we observed that AT tissue contained much less INKT cells than the liver which is a known reservoir of this cell type. Accordingly, mice specifically lacking iNKT cells did not differ in their kinetics of glucose clearance compared to wildtype controls. Interestingly, although expression of inflammatory markers in AT did not differ between the groups homeostasis iNKT cell-deficient mice was altered evidenced by lower AT weight, smaller adipocytes, accelerated lipogenesis, increased expression of hormone-sensitive lipase, and accelerated basal lipolysis. These data demonstrate that iNKT cells which normally reside in the liver can impact metabolic changes in other organs while their presence in such organs (e.g., AT) is not required.

 

Outlook:

We currently focus our efforts to investigate the phenotype and function of T cell subsets in different stages of atherosclerosis while exploring the kinetics of their appearance. Mechanistic studies will try to reveal the underlying mechanisms and unexpected consequences, such as changes in lipid metabolism, will be investigated. In addition, we examine the function of the non-classical co-stimulatory molecules CD27, CD70, GITR, and CTLA-4 in different stages and models of atherosclerosis. Many synergies are shared with Esther Lutgens, main interest of whom is the role of the classical co-stimulator CD40/CD40L in vascular biology and obesity.

 

Arbeitsgruppenleiter:

Dr. rer. nat. Norbert Gerdes

 
 
IPEKlogo

Direktor: Prof. Dr. med. Christian Weber

Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten (IPEK)

 

Pettenkoferstraße 8a & 9

80336 München

 

Tel.: 089-4400-54351

Fax: 089-4400-54352

Mail: Kreislaufinstitut@med.uni-muenchen.de

 

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