Oral Presentation MIN Spring Retreat 2023

ID3 and c-Kit define the stem-like potential of T cells and their response to chronic infection and cancer (#12)

Amania A. Sheikh 1 , Dane Newman 2 , Sarah S. Gabriel 1 , David Chisanga 3 , Justine Seow 1 4 , Lifen Wen 1 , Annika Poch 1 , Thi Minh Hanh T. Nguyen 1 , Chun-Hsi Su 1 , Carlson Tusi 1 , Catarina Gago da Graca 1 , Thomas Burn 1 , Laura K. Mackay 1 , Wei Shi 3 , Jan Schroeder 4 , Ricky W. Johnstone 2 , Axel Kallies 1 , Daniel T. Utzschneider 1
  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  2. Cancer Biology and Therapeutics, Peter MacCallum Cancer Centre, Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  3. Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
  4. Computational Sciences Initiative (CSI), The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia

CD8+ T cell responses to chronic infection and cancer are sustained by stem-like precursors of exhausted T (Tpex) cells that express high levels of memory-related transcriptional regulators including TCF1 and ID3. Here, we identify a critical role for ID3 in promoting continuous differentiation of Tpex cells to sustain ongoing T cell responses in chronic infection. Mechanistically, we show that ID3 regulates the developmental progression of stem-like Tpex cells expressing CD62L and MYB to Tpex cells marked by expression of the tyrosine-protein kinase c-Kit, which itself promoted T cell expansion and effector differentiation. Finally, we demonstrate that ID3 expression in memory T cells that develop after acute infection or T cells activated in the presence of IL-18 promoted the generation of Tpex cells and thus superior T cell responses when challenged with chronic infection or cancer. Thus, we identify a critical role for ID3 in promoting functional and long-lasting T cell responses in chronic infection and cancer.