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An autoimmune stem-like CD8 T cell population drives type 1 diabetes

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Listed:
  • Sofia V. Gearty

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Friederike Dündar

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Paul Zumbo

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Gabriel Espinosa-Carrasco

    (Memorial Sloan Kettering Cancer Center)

  • Mojdeh Shakiba

    (Memorial Sloan Kettering Cancer Center)

  • Francisco J. Sanchez-Rivera

    (Memorial Sloan Kettering Cancer Center)

  • Nicholas D. Socci

    (Memorial Sloan Kettering Cancer Center)

  • Prerak Trivedi

    (Memorial Sloan Kettering Cancer Center)

  • Scott W. Lowe

    (Memorial Sloan Kettering Cancer Center)

  • Peter Lauer

    (Aduro Biotech)

  • Neeman Mohibullah

    (Memorial Sloan Kettering Cancer Center)

  • Agnes Viale

    (Memorial Sloan Kettering Cancer Center)

  • Teresa P. DiLorenzo

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Doron Betel

    (Weill Cornell Medicine
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Andrea Schietinger

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

Abstract

CD8 T cell-mediated autoimmune diseases result from the breakdown of self-tolerance mechanisms in autoreactive CD8 T cells1. How autoimmune T cell populations arise and are sustained, and the molecular programmes defining the autoimmune T cell state, are unknown. In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells. Here we followed the fate of β-cell-specific CD8 T cells in non-obese diabetic mice throughout the course of type 1 diabetes. We identified a stem-like autoimmune progenitor population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators. pLN autoimmune mediators migrate to the pancreas, where they differentiate further and destroy β-cells. Whereas transplantation of as few as 20 autoimmune progenitors induced type 1 diabetes, as many as 100,000 pancreatic autoimmune mediators did not. Pancreatic autoimmune mediators are short-lived, and stem-like autoimmune progenitors must continuously seed the pancreas to sustain β-cell destruction. Single-cell RNA sequencing and clonal analysis revealed that autoimmune CD8 T cells represent unique T cell differentiation states and identified features driving the transition from autoimmune progenitor to autoimmune mediator. Strategies aimed at targeting the stem-like autoimmune progenitor pool could emerge as novel and powerful immunotherapeutic interventions for type 1 diabetes.

Suggested Citation

  • Sofia V. Gearty & Friederike Dündar & Paul Zumbo & Gabriel Espinosa-Carrasco & Mojdeh Shakiba & Francisco J. Sanchez-Rivera & Nicholas D. Socci & Prerak Trivedi & Scott W. Lowe & Peter Lauer & Neeman , 2022. "An autoimmune stem-like CD8 T cell population drives type 1 diabetes," Nature, Nature, vol. 602(7895), pages 156-161, February.
  • Handle: RePEc:nat:nature:v:602:y:2022:i:7895:d:10.1038_s41586-021-04248-x
    DOI: 10.1038/s41586-021-04248-x
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    Cited by:

    1. Kateryna Onyshchenko & Ren Luo & Elena Guffart & Simone Gaedicke & Anca-Ligia Grosu & Elke Firat & Gabriele Niedermann, 2023. "Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Ting Zhong & Xinyu Li & Kang Lei & Rong Tang & Qiaolin Deng & Paul E Love & Zhiguang Zhou & Bin Zhao & Xia Li, 2024. "TGF-β-mediated crosstalk between TIGIT+ Tregs and CD226+CD8+ T cells in the progression and remission of type 1 diabetes," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Shenqiang Wang & Ying Zhang & Yanfang Wang & Yinxian Yang & Sheng Zhao & Tao Sheng & Yuqi Zhang & Zhen Gu & Jinqiang Wang & Jicheng Yu, 2023. "An in situ dual-anchoring strategy for enhanced immobilization of PD-L1 to treat autoimmune diseases," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Keiichiro Mine & Seiho Nagafuchi & Satoru Akazawa & Norio Abiru & Hitoe Mori & Hironori Kurisaki & Kazuya Shimoda & Yasunobu Yoshikai & Hirokazu Takahashi & Keizo Anzai, 2024. "TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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