Immunologists in the Winau Lab are most excited about the discovery of basic mechanisms that explain how the immune system functions. Over the years, we added to the passion for basic science a strong interest in identifying targets for possible translation to future immunotherapies. Our research program is quite diverse, ranging from classical cellular immunology using mouse models, studies in the human system and structural biology, over viral infection models and cell biology using live microscopy, to molecular biology and global epigenetic analyses. To reduce it to a common denominator, our work can be described as “antigen presentation, T cell biology, and the role of lipids in Immunology”. Below we would like to highlight some specific research topics.
A. Lipid presentation and inflammatory disease
In contrast to MHC proteins, CD1 molecules present lipid antigens to T lymphocytes. We study the role of CD1a on Langerhans cells in skin inflammation, using mouse models of contact dermatitis and psoriasis as well as patient samples. Notably, the treatment with CD1a blocking antibodies is able to abrogate inflammation of the skin. Therefore, we currently develop new CD1a-based drugs for future therapy of inflammatory skin diseases.
Interestingly, CD1a can also be expressed in other organs beyond the skin. Accordingly, current experiments investigate the role of CD1a in inflammatory bowel disease. Taken together, we consider CD1-mediated immune responses as a general principle of inflammation.
B. Regulation of membrane composition and T cell exhaustion
The distribution of membrane lipids affects protein function, such as recruitment and signal transduction. We are interested in the active regulation of the lipid microenvironment and how this influences T cell activation. Studying lipid scramblase, a protein that transports anionic phospholipids across membranes, we show that lack of scrambling induces severe T cell exhaustion. This leads to failure to control virus burden in models of chronic viral infection.
In follow-up work, we try to inducibly activate scramblase to break T cell exhaustion. We aim at translating scramblase modulation to settings of chronic viral infection as well as cancer in order to establish a new form of immunotherapy.
C. Tissue-specific immunity
The lab has a long-standing interest in organ-specific immune responses, such as the Immunology of the liver. Abundant among liver lymphocytes are Natural Killer T (NKT) cells that recognize CD1d molecules and behave in an innate-like fashion, producing large amounts of different cytokines upon activation. This quick response pattern endows NKT cells with regulatory properties. In addition to their epigenetic landscape, we elucidate novel enzymatic pathways that generate the endogenous lipid antigens required for thymic selection and peripheral activation of NKT cells. These new enzyme candidates also allow us to study their metabolic impact on NKT cell-mediated protection against cancer.
Another liver-intrinsic cell type is the hepatic stellate cell that has important functions in storage of vitamin A and the generation of liver fibrosis. We develop new genetic mouse models to specifically modulate stellate cell functions in vivo. Using these targeting strategies, we aim to test the impact of stellate cells on i) the migratory properties of lymphoid cells to home to the gut and the thymus, ii) regulatory T cells (Treg) and oral tolerance, and iii) immunological memory of the liver.
Other pilot studies in the lab include the exploration of the HIV reservoir and epigenetic inheritance.
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