Using single-cell RNA sequencing, Gago da Graça, Sheikh, and Newman et al. investigated developmental relationships between stem-like memory T cells and Tpex cells, and their roles in infection and cancer. ID3 expression identified stem-like T cells during acute infection, which generated functional, self-renewing Tpex cells required for sustaining T cell responses in chronic infection or cancer. Loss of ID3 impaired maintenance of CD8+ T cell immunity. IL-1 family members (IL-36β and IL-18) promoted ID3+ T cell formation with enhanced capacity to sustain CD8+ T cell responses in chronic infection and mediate superior tumor control.
Contributed by Katherine Turner
ABSTRACT: Stem-like T cells are attractive immunotherapeutic targets in patients with cancer given their ability to proliferate and differentiate into effector progeny. Thus, identifying T cells with enhanced stemness and understanding their developmental requirements are of broad clinical and therapeutic interest. Here, we demonstrate that during acute infection, the transcriptional regulator inhibitor of DNA binding 3 (ID3) identifies stem-like T cells that are uniquely adapted to generate precursors of exhausted T (Tpex) cells in response to chronic infection or cancer. Expression of ID3 itself enables Tpex cells to sustain T cell responses in chronic infection or cancer, whereas loss of ID3 results in impaired maintenance of CD8 T cell immunity. Furthermore, we demonstrate that interleukin-1 (IL-1) family members, including IL-36_ and IL-18, promote the generation of ID3(+) T cells that mediate superior tumor control. Overall, we identify ID3 as a common denominator of stem-like T cells in both acute and chronic infections that is specifically required to sustain T cell responses to chronic stimulation.
Author Info: (1) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (2) Department of Microbiology and
Author Info: (1) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (2) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (3) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia. (4) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (5) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (6) Department of Pathology, Northwestern University, Chicago, IL, USA. (7) Department of Pathology, Northwestern University, Chicago, IL, USA. (8) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (9) Olivia Newton-John Cancer Research Institute, Heidelberg, Australia. (10) Computational Sciences Initiative (CSI), Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (11) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (12) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (13) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (14) Olivia Newton-John Cancer Research Institute, Heidelberg, Australia. (15) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (16) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia. (17) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (18) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (19) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (20) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (21) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (22) Olivia Newton-John Cancer Research Institute, Heidelberg, Australia. (23) Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, Birmingham B15 2TT, UK. (24) Olivia Newton-John Cancer Research Institute, Heidelberg, Australia. School of Cancer Medicine, La Trobe University, Heidelberg, Australia. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia. (25) Department of Pathology, Northwestern University, Chicago, IL, USA. (26) Computational Sciences Initiative (CSI), Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (27) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia. (28) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia. (29) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.
