Oral Presentation Melbourne Immunotherapy Network Winter Symposium 2021

Regulation of stemness and exhaustion of CD8+ T cells during chronic infection (#9)

Carlson Tsui 1 , Lorentz Kretschmer 2 , Svenja Rapelius 2 , Sarah S. Gabriel 1 , David Chisanga 3 4 5 6 , Konrad Knöpper 7 , Daniel T. Utzschneider 1 , Simone Nüssing 8 9 , Yang Liao 3 4 5 6 , Teisha Teisha 1 , Santiago Torres 1 , Stephen Wilcox 3 , Stephen L. Nutt 3 , Dietmar Zehn 2 , Ian Parish 8 9 , Wolfgang Kastenmüller 7 , Wei Shi 3 4 6 10 , Axel Kallies 1
  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia
  2. Technical University Munich, Munich, Germany
  3. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
  4. Department of Medical Biology, University of Melbourne, Melbourne, Australia
  5. School of Cancer Medicine, La Trobe University, Heidelberg, Australia
  6. Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
  7. Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius- Maximilians-Universität Würzburg, Würzburg, Germany
  8. Peter MacCallum Cancer Centre, Melbourne, Australia
  9. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  10. School of Computing and Information Systems, University of Melbourne, Melbourne, Australia

Immunity to chronic viral infection and cancer is tightly associated with CD8+ T cell exhaustion, which is characterized by high expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and impaired effector function. Understanding the molecular regulation of T cell exhaustion is critical for the development of new immunotherapies. Chronically activated T cells are maintained by precursors of exhausted T (TPEX) cells that express the transcription factor TCF1, self-renew and give rise to TCF-1– exhausted effector T (TEX) cells; the factors that control these processes, however, are poorly understood. Using single cell RNAseq we describe a novel functionally important subset of cells within the TPEX cell compartment that selectively preserves the long-term self-renewal capacity and multipotency of antigen-specific T cells during chronic infection. Furthermore, we identify a transcription factor that is essential for both the self-renewal capacity of TPEX cells and the induction of key features of T cell exhaustion. Finally, we show that the novel transcriptionally distinct TPEX cell subset exclusively mediates T cell proliferation during PD-1 checkpoint inhibition, making it an attractive target for new immunotherapeutic strategies.