Unravelling the role of CD46 in T cell fate decisions

• Applicant: Dr. Tilo Freiwald
• Subject Area: Immunology ; Nephrology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431725001

• Final Report Year: 2023

Final Report Abstract

The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. In the last few years, it has become apparent that complement is not restricted to the extracellular space but is also present within immune cells as an autocrine system. The cell surface receptor CD46 is a key regulatory molecule in this newly discovered autocrine or local system, particularly in T cells, which are key mediators of human autoimmunity and highly responsive to complement. In this project we investigated how CD46 signalling drives T cell fate decisions. We found that activation of CD46 drives a T cell shutdown program that is dependent on Vitamin D signalling. This process was primed by dynamic changes in the epigenetic landscape of CD4+ T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with Vitamin D receptor shaped the transcriptional response to Vitamin D. This specific signature was found to be impaired in T cells from patients with COVID-19. In a follow up study, we found that in patients with COVID-19, lung epithelial cells locally produce and activate complement C3 a ligand of CD46. Locally activated immune cells displayed a CD46 activation signature. JAK-STAT-Inhibition was found to reduce complement activation and interferon related genes and thus could potentially have clinical application severe COVID-19. Understanding the molecular means by which CD46 determines T cell behaviour is essential for identifying and appropriately targeting this pathway for immunomodulation in the context of inflammatory diseases in human.

Publications

• Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science, 371(6526).
  Break, Timothy J.; Oikonomou, Vasileios; Dutzan, Nicolas; Desai, Jigar V.; Swidergall, Marc; Freiwald, Tilo; Chauss, Daniel; Harrison, Oliver J.; Alejo, Julie; Williams, Drake W.; Pittaluga, Stefania; Lee, Chyi-Chia R.; Bouladoux, Nicolas; Swamydas, Muthulekha; Hoffman, Kevin W.; Greenwell-Wild, Teresa; Bruno, Vincent M.; Rosen, Lindsey B.; Lwin, Wint ... & Lionakis, Michail S.
  
• Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells. Nature Immunology, 23(1), 62-74.
  Chauss, Daniel; Freiwald, Tilo; McGregor, Reuben; Yan, Bingyu; Wang, Luopin; Nova-Lamperti, Estefania; Kumar, Dhaneshwar; Zhang, Zonghao; Teague, Heather; West, Erin E.; Vannella, Kevin M.; Ramos-Benitez, Marcos J.; Bibby, Jack; Kelly, Audrey; Malik, Amna; Freeman, Alexandra F.; Schwartz, Daniella M.; Portilla, Didier; Chertow, Daniel S. ... & Afzali, Behdad
  
• Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation. Science Immunology, 6(66).
  Niyonzima, Nathalie; Rahman, Jubayer; Kunz, Natalia; West, Erin E.; Freiwald, Tilo; Desai, Jigar V.; Merle, Nicolas S.; Gidon, Alexandre; Sporsheim, Bjørnar; Lionakis, Michail S.; Evensen, Kristin; Lindberg, Beate; Skagen, Karolina; Skjelland, Mona; Singh, Parul; Haug, Markus; Ruseva, Marieta M.; Kolev, Martin; Bibby, Jack ... & Kemper, Claudia
  
• Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics. Advances in Immunology, 1-81.
  Freiwald, Tilo & Afzali, Behdad
  
• Response to Comments on “Aberrant type 1 immunity drives susceptibility to mucosal fungal infections”. Science, 373(6561).
  Break, Timothy J.; Oikonomou, Vasileios; Dutzan, Nicolas; Desai, Jigar V.; Swidergall, Marc; Freiwald, Tilo; Chauss, Daniel; Harrison, Oliver J.; Alejo, Julie; Williams, Drake W.; Pittaluga, Stefania; Lee, Chyi-Chia R.; Bouladoux, Nicolas; Swamydas, Muthulekha; Hoffman, Kevin W.; Greenwell-Wild, Teresa; Bruno, Vincent M.; Rosen, Lindsey B.; Lwin, Wint ... & Lionakis, Michail S.
  
• SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation. Science Immunology, 6(58).
  Yan, Bingyu; Freiwald, Tilo; Chauss, Daniel; Wang, Luopin; West, Erin; Mirabelli, Carmen; Zhang, Charles J.; Nichols, Eva-Maria; Malik, Nazish; Gregory, Richard; Bantscheff, Marcus; Ghidelli-Disse, Sonja; Kolev, Martin; Frum, Tristan; Spence, Jason R.; Sexton, Jonathan Z.; Alysandratos, Konstantinos D.; Kotton, Darrell N.; Pittaluga, Stefania ... & Kazemian, Majid
  
• Systematic single-cell pathway analysis to characterize early T cell activation. Cell Reports, 41(8), 111697.
  Bibby, Jack A.; Agarwal, Divyansh; Freiwald, Tilo; Kunz, Natalia; Merle, Nicolas S.; West, Erin E.; Singh, Parul; Larochelle,;re; Chinian, Fariba; Mukherjee, Somabha; Afzali, Behdad; Kemper, Claudia & Zhang, Nancy R.
  
• C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection. Cell, 186(13), 2802-2822.e22.
  Desai, Jigar V.; Kumar, Dhaneshwar; Freiwald, Tilo; Chauss, Daniel; Johnson, Melissa D.; Abers, Michael S.; Steinbrink, Julie M.; Perfect, John R.; Alexander, Barbara; Matzaraki, Vasiliki; Snarr, Brendan D.; Zarakas, Marissa A.; Oikonomou, Vasileios; Silva, Lakmali M.; Shivarathri, Raju; Beltran, Emily; Demontel, Luciana Negro; Wang, Luopin; Lim, Jean K. ... & Lionakis, Michail S.
  
• Clinical Immunology.
  Afzali, B.; Waldman, M. & Freiwald, T. (Eds.)