Glycoprotein A repetitions predominant, a Treg-specific molecule, in autoimmune inflammation
Final Report Abstract
Autoimmune diseases develop on the background of autoimmune reactions when peripheral tolerance mechanisms fail and thus immune reactions against endogenous structures may persist and ultimately lead to the destruction of organs or organ structures. One, if not the most important, mechanism of peripheral tolerance is the active attenuation of a potentially aggressive autoimmune response by regulatory T cells. Regulatory T cells are CD4 positive helper T cells, express a chain of the interleukin-2 receptor (CD25) at high density, and are characterized by their specific transcription factor Foxp3. Foxp3 is a necessary requirement for the development of regulatory T cells as well as for the function of these cells. If Foxp3 is missing, e.g. in genetically modified mice (Scurfy) or in humans after spontaneous mutation of Foxp3 (IPEX), no regulatory T cells are generated and the affected organisms develop fulminant polytopic autoimmune diseases. Even in human autoimmune diseases that do not progress so dramatically, such as rheumatoid arthritis or inflammatory bowel diseases, decreased functionality of Foxp3 is thought to contribute to a decreased regulatory capacity of regulatory T cells, enabling the transition from physiological autoimmune responses to pathological autoimmune diseases. Mechanisms underlying such reduced functional capacity of Foxp3 may therefore contribute to a pathophysiological understanding of the development of autoimmune diseases. In the research project summarized here, we have characterized a surface molecule specifically expressed on regulatory T cells, glycoprotein A repetitions predominant (GARP), and were able to show that GARP controls the stability of Foxp3. We could identify patients with mutations in the GARP gene that result in decreased expression of GARP on the surface of their regulatory T cells. Foxp3 expressed in the regulatory T cells of these patients has significantly decreased stability and half-life, and the regulatory T cells of these patients show a decreased ability to terminate immune responses. Clinically, these patients suffer from polytopic autoimmune disorders. Because GARP is a receptor for latent TGF-b, we examined the expression of TGF-b-dependent genes in the regulatory T cells of these patients and were able to show that it is altered. One of these gene products whose expression is suppressed by TGF-b is histone deacetylase 9 (HDAC9). HDAC9 is found at higher levels in GARP-deficient regulatory T cells. Functionally, HDAC9 deacetylates, among others, Foxp3, which in turn leads to its decay – and consequently to an instability of regulatory T cells. The addition of TGF-b into the medium reduced HDAC9 expression in GARP-deficient regulatory T cells, increased Foxp3 stability and improved the functional capacity of these cells. We were thus able to demonstrate a molecular mechanism of regulatory T cell stability mediated by the molecule GARP characterized in the project, which plays a central role in the prevention of autoimmune diseases.
Publications
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Cytotoxic T cells go awry in inclusion body myositis. Brain, 139(5), 1312-1314.
Hohlfeld, Reinhard & Schulze-Koops, Hendrik
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Methylation of an intragenic alternative promoter regulates transcription of GARP. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1859(2), 223-234.
Haupt, Sonja; Söntgerath, Viktoria Sophie Apollonia; Leipe, Jan; Schulze-Koops, Hendrik & Skapenko, Alla
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Defining Epigenetic Regulation of the Interleukin-9 Gene by Chromatin Immunoprecipitation. Methods in Molecular Biology, 179-187. Springer New York.
Skapenko, Alla & Schulze-Koops, Hendrik
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P022 Checkpoint inhibitors activate store-operated CA2+ entry and ERK1/2 signalling and promote TH17 differentiation. Annals of the Rheumatic Diseases, 77, A23.
Zapp, B.; Lehmkuhl, P.; Schulze-Koops, H. & Skapenko, A.
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Dysregulated immunity in PID patients with low GARP expression on Tregs due to mutations in LRRC32. Cellular & Molecular Immunology, 18(7), 1677-1691.
Lehmkuhl, Peter; Gentz, Magdalena; Garcia, de Otezya Andres Caballero; Grimbacher, Bodo; Schulze-Koops, Hendrik & Skapenko, Alla
