Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression

Catarina Gago da Graça; Amania A. Sheikh; Dane M. Newman; Lifen Wen; Sining Li; Jian Shen; Yuqi Zhang; Sarah S. Gabriel; David Chisanga; Justine Seow; Annika Poch; Lisa Rausch; Minh Hanh T. Nguyen; Jayendra Singh; Chun Hsi Su; Leonie A. Cluse; Carlson Tsui; Thomas N. Burn; Simone L. Park; Bianca Von Scheidt; Laura K. Mackay; Ajithkumar Vasanthakumar; David Bending; Wei Shi; Weiguo Cui; Jan Schröder; Ricky W. Johnstone; Axel Kallies; Daniel T. Utzschneider

doi:10.1126/sciimmunol.adn1945

Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression

Catarina Gago da Graça, Amania A. Sheikh, Dane M. Newman, Lifen Wen, Sining Li, Jian Shen, Yuqi Zhang, Sarah S. Gabriel, David Chisanga, Justine Seow, Annika Poch, Lisa Rausch, Minh Hanh T. Nguyen, Jayendra Singh, Chun Hsi Su, Leonie A. Cluse, Carlson Tsui, Thomas N. Burn, Simone L. Park, Bianca Von ScheidtLaura K. Mackay, Ajithkumar Vasanthakumar, David Bending, Wei Shi, Weiguo Cui, Jan Schröder, Ricky W. Johnstone^*, Axel Kallies^*, Daniel T. Utzschneider^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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-36β 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.

Original language	English (US)
Article number	eadn1945
Journal	Science Immunology
Volume	10
Issue number	103
DOIs	https://doi.org/10.1126/sciimmunol.adn1945
State	Published - Jan 2025

Funding

We thank S. Bedoui and members of the Utzschneider, Kallies, and Johnstone laboratories for helpful discussions. We acknowledge the Melbourne Cytometry Platform for the provision of flow cytometry services, the NIH Tetramer Facility for providing tetramer, the WEHI Advance genomics platform team for sequencing, and the Animal Facility, Genotyping Core, and Flow Cytometry Facility of the Peter MacCallum Cancer Centre. Funding: This work was supported by the National Health and Medical Research Council of Australia (NHMRC) Investigator Grant (no. 1194779 to D.T.U., no. 2017420 to A.K., no. 2016820 to R.W.J., and no. 1175626 to S.L.P.) and Ideas Grant (no. 2004333 to A.K. and C.T.), the CASS Foundation (no. 10055 to D.T.U.), the Cancer Council Victoria and the Kids\u2019 Cancer Project (both to R.W.J.), the UK Research & Innovation (no. MR/V009052/1 to D.B.), an Early Career Research Grant from the University of Melbourne (to A.A.S.), the Clive and Vera Ramaciotti Foundation (to D.T.U.), the J & M Wright Foundation (fellowship to J. Schr\u00F6der), a CSL Centenary Fellowship (to D.T.U.), and University of Melbourne Graduate Research Scholarships (to C.G.d.G., S.L., and M.-H.T.N.).

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Gago da Graça, C., Sheikh, A. A., Newman, D. M., Wen, L., Li, S., Shen, J., Zhang, Y., Gabriel, S. S., Chisanga, D., Seow, J., Poch, A., Rausch, L., Nguyen, M. H. T., Singh, J., Su, C. H., Cluse, L. A., Tsui, C., Burn, T. N., Park, S. L., ... Utzschneider, D. T. (2025). Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression. Science Immunology, 10(103), Article eadn1945. https://doi.org/10.1126/sciimmunol.adn1945

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title = "Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression",

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-36β 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 = "\{Gago da Gra{\c c}a\}, Catarina and Sheikh, \{Amania A.\} and Newman, \{Dane M.\} and Lifen Wen and Sining Li and Jian Shen and Yuqi Zhang and Gabriel, \{Sarah S.\} and David Chisanga and Justine Seow and Annika Poch and Lisa Rausch and Nguyen, \{Minh Hanh T.\} and Jayendra Singh and Su, \{Chun Hsi\} and Cluse, \{Leonie A.\} and Carlson Tsui and Burn, \{Thomas N.\} and Park, \{Simone L.\} and \{Von Scheidt\}, Bianca and Mackay, \{Laura K.\} and Ajithkumar Vasanthakumar and David Bending and Wei Shi and Weiguo Cui and Jan Schr{\"o}der and Johnstone, \{Ricky W.\} and Axel Kallies and Utzschneider, \{Daniel T.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors, some rights reserved.",

year = "2025",

month = jan,

doi = "10.1126/sciimmunol.adn1945",

language = "English (US)",

volume = "10",

journal = "Science Immunology",

issn = "2470-9468",

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Gago da Graça, C, Sheikh, AA, Newman, DM, Wen, L, Li, S, Shen, J, Zhang, Y, Gabriel, SS, Chisanga, D, Seow, J, Poch, A, Rausch, L, Nguyen, MHT, Singh, J, Su, CH, Cluse, LA, Tsui, C, Burn, TN, Park, SL, Von Scheidt, B, Mackay, LK, Vasanthakumar, A, Bending, D, Shi, W, Cui, W, Schröder, J, Johnstone, RW, Kallies, A & Utzschneider, DT 2025, 'Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression', Science Immunology, vol. 10, no. 103, eadn1945. https://doi.org/10.1126/sciimmunol.adn1945

TY - JOUR

T1 - Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression

AU - Gago da Graça, Catarina

AU - Sheikh, Amania A.

AU - Newman, Dane M.

AU - Wen, Lifen

AU - Li, Sining

AU - Shen, Jian

AU - Zhang, Yuqi

AU - Gabriel, Sarah S.

AU - Chisanga, David

AU - Seow, Justine

AU - Poch, Annika

AU - Rausch, Lisa

AU - Nguyen, Minh Hanh T.

AU - Singh, Jayendra

AU - Su, Chun Hsi

AU - Cluse, Leonie A.

AU - Tsui, Carlson

AU - Burn, Thomas N.

AU - Park, Simone L.

AU - Von Scheidt, Bianca

AU - Mackay, Laura K.

AU - Vasanthakumar, Ajithkumar

AU - Bending, David

AU - Shi, Wei

AU - Cui, Weiguo

AU - Schröder, Jan

AU - Johnstone, Ricky W.

AU - Kallies, Axel

AU - Utzschneider, Daniel T.

PY - 2025/1

Y1 - 2025/1

N2 - 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-36β 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.

AB - 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-36β 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.

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DO - 10.1126/sciimmunol.adn1945

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ER -

Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression

Abstract

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UN SDGs

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