Unravelling the role of CD46 in T cell fate decisions

  • Freiwald, Tilo (Principal Investigator (PI))
  • Kemper, Claudia (Supervisor)
  • Afzali, Behdad (Supervisor)

Project: DFG Individual ProjectsDFG Scholarships: Research Fellowships

Project Details

Description

The complement system is a component of the immune system used to recognise and remove invading micro-organisms. As such, it is undeniably of critical importance to immunity and host defense. Hyperactivity of the complement system underlies a number of diseases of humans, such as systemic lupus erythematosus, where there is a need for new, effective and low toxicity treatments.Complement has been traditionally viewed as a serum-restricted system. 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 system, particularly in T cells, which are key mediators of human autoimmunity and highly responsive to complement. This single molecule causes T cells to first take on inflammatory functions in order to eradicate infections and then to shut down those pathways in order to dampen inflammation and allow restoration of tissue integrity. How CD46 signaling achieves these dual functions is poorly understood and could be key to developing new drug therapies.In this application I propose to study the cell signaling events initiated by engagement of CD46 and uncover how CD46 signals are integrated in the nucleus to drive gene expression and determine disparate T cell functions. We aim to uncover the genes directly bound and regulated by CD46 (Aim 1), the signaling cascade initiated on CD46 engagement (Aim 2) and the outcomes of those events at the single cell level (Aim 3). Broadly, these will be achieved by leveraging unique reagents, cutting-edge massive parallel sequencing, cell and molecular technologies. In the year I have already spent at the National Institutes of Health I have generated the preliminary data to support these aims. 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 of humans.

Key findings

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.
Statusfinished
Effective start/end date01.01.1931.12.22

UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This project contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 2.21-05 Immunology

Funding Institution

  • DFG: German Research Association

ASJC Subject Areas

  • Immunology

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  • C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection

    Desai, J. V., Kumar, D., Freiwald, T., Chauss, D., Johnson, M. D., Abers, M. S., Steinbrink, J. M., Perfect, J. R., Alexander, B., Matzaraki, V., Snarr, B. D., Zarakas, M. A., Oikonomou, V., Silva, L. M., Shivarathri, R., Beltran, E., Demontel, L. N., Wang, L., Lim, J. K. & Launder, D. & 11 others, Conti, H. R., Swamydas, M., McClain, M. T., Moutsopoulos, N. M., Kazemian, M., Netea, M. G., Kumar, V., Köhl, J., Kemper, C., Afzali, B. & Lionakis, M. S., 22.06.2023, In: Cell. 186, 13, p. 2802-2822.e22

    Research output: Journal ArticlesJournal articlesResearchpeer-review

    5 Citations (Scopus)