GSH-dependent regulation of IL-17-producing CD8+ T cells in autoimmune inflammation of the central nervous system

• Applicant: Professorin Dr. Magdalena Huber
• Subject Area: Immunology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414259009

• Final Report Year: 2023

Final Report Abstract

During the founding period, as applied, we focused on the function and regulation of IL-17-producing CD8+ (Tc17) cells in autoimmune inflammation of the central nervous system (CNS). We revealed a specific regulation of Tc17 cells by dimethyl fumarate (DMF), an oral drug applied for treatment of Multiple Sclerosis (MS), which in glutathione(GSH)-dependent manner selectively suppressed Tc17 differentiation, thereby preventing MS progression. In this manuscript, we also presented evidence for differential regulation of Tc17 and Th17 cells giving reason for further work aiming understanding a specific role of these cells in pathologic conditions. Thus, in a further collaborative work we described a context dependent, dichotomous role for natrium chloride (NaCl) in shaping Th17 cell pathogenicity in autoimmune inflammation of the CNS. Since IL-17-producing cells are detectable in cancer, we extended our analyses to the role of Th17 and Tc17 cells in lung cancer and pancreatic cancer, respectively. The obtained results were published in a collaborative work for lung cancer and in mainly by our group performed experiments in pancreatic cancer. Finally, we summarized the knowledge on IL-17-producing CD8+ T cells in a review article.

Publications

• IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nature Communications, 10(1).
  Lückel, Christina; Picard, Felix; Raifer, Hartmann; Campos, Carrascosa Lucia; Guralnik, Anna; Zhang, Yajuan; Klein, Matthias; Bittner, Stefan; Steffen, Falk; Moos, Sonja; Marini, Federico; Gloury, Renee; Kurschus, Florian C.; Chao, Ying-Yin; Bertrams, Wilhelm; Sexl, Veronika; Schmeck, Bernd; Bonetti, Lynn; Grusdat, Melanie ... & Huber, Magdalena
  
• Microenvironmental Th9 and Th17 lymphocytes induce metastatic spreading in lung cancer. Journal of Clinical Investigation, 130(7), 3560-3575.
  Salazar, Ylia; Zheng, Xiang; Brunn, David; Raifer, Hartmann; Picard, Felix; Zhang, Yajuan; Winter, Hauke; Guenther, Stefan; Weigert, Andreas; Weigmann, Benno; Dumoutier, Laure; Renauld, Jean-Christophe; Waisman, Ari; Schmall, Anja; Tufman, Amanda; Fink, Ludger; Brüne, Bernhard; Bopp, Tobias; Grimminger, Friedrich ... & Savai, Rajkumar
  
• Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments. Journal of Clinical Investigation, 130(9), 4587-4600.
  Matthias, Julia; Heink, Sylvia; Picard, Felix; Zeiträg, Julia; Kolz, Anna; Chao, Ying-Yin; Soll, Dominik; de Almeida Gustavo, P.; Glasmacher, Elke; Jacobsen, Ilse D.; Riedel, Thomas; Peters, Anneli; Floess, Stefan; Huehn, Jochen; Baumjohann, Dirk; Huber, Magdalena; Korn, Thomas & Zielinski, Christina E.
  
• Tc17 biology and function: Novel concepts. European Journal of Immunology, 50(9), 1257-1267.
  Lückel, Christina; Picard, Felix. S. R. & Huber, Magdalena
  
• IL-17A-producing CD8+ T cells in pancreatic cancer. Nature Reviews Gastroenterology & Hepatology, 20(4), 202-202.
  Kotsiliti, Eleni