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

Immunology and Immunotherapy

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

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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
Pages (from-to)	eadn1945
Journal	Science Immunology
Volume	10
Issue number	103
DOIs	https://doi.org/10.1126/sciimmunol.adn1945
Publication status	Published - 31 Jan 2025

Keywords

Inhibitor of Differentiation Proteins/genetics
Animals
Mice
Mice, Inbred C57BL
CD8-Positive T-Lymphocytes/immunology
Immunologic Memory/immunology
Mice, Knockout
Humans
Memory T Cells/immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/sciimmunol.adn1945

daGraçaC2025StemAccepted author manuscript, 27 MBLicence: Creative Commons: Attribution (CC BY)

Negative feedback control of T cells in tolerance and cancer - from pathways to biomarkers
Bending, D. (Principal Investigator)
Medical Research Council
1/02/21 → 31/01/26
Project: Research Councils

Cite this

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), eadn1945. https://doi.org/10.1126/sciimmunol.adn1945

@article{6e7e13e9c5544eab970827e13a44ef66,

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. ",

keywords = "Inhibitor of Differentiation Proteins/genetics, Animals, Mice, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes/immunology, Immunologic Memory/immunology, Mice, Knockout, Humans, Memory T Cells/immunology",

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 Chun-Hsi Su 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.}",

year = "2025",

month = jan,

day = "31",

doi = "10.1126/sciimmunol.adn1945",

language = "English",

volume = "10",

pages = "eadn1945",

journal = "Science Immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "103",

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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, M-HT, Singh, J, Su, C-H, 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, pp. 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 - 2025/1/31

Y1 - 2025/1/31

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.

KW - Inhibitor of Differentiation Proteins/genetics

KW - Animals

KW - Mice

KW - Mice, Inbred C57BL

KW - CD8-Positive T-Lymphocytes/immunology

KW - Immunologic Memory/immunology

KW - Mice, Knockout

KW - Humans

KW - Memory T Cells/immunology

U2 - 10.1126/sciimmunol.adn1945

DO - 10.1126/sciimmunol.adn1945

M3 - Article

C2 - 39888981

SN - 2470-9468

VL - 10

SP - eadn1945

JO - Science Immunology

JF - Science Immunology

IS - 103

ER -

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

Abstract

Keywords

UN SDGs

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Negative feedback control of T cells in tolerance and cancer - from pathways to biomarkers

Cite this