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

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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 programs defining the autoimmune T cell state are unknown. In Type 1 diabetes (T1D), beta cell–specific CD8 T cells destroy insulin-producing beta cells. We followed the fate of beta cell–specific CD8 T cells in non-obese diabetic mice throughout the course of T1D. We identified a stem-like autoimmune progenitor (AP) population in the pancreatic draining lymph node (pLN), which self-renews and gives rise to pLN autoimmune mediators (AM). pLN AM migrate to the pancreas, where they differentiate further and destroy beta cells. While transplantation of as few as 20 AP induced T1D, as many as 100,000 pancreatic AM failed to do so. Pancreatic AM are short-lived and stem-like AP must continuously seed the pancreas to sustain beta 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 AP to AM. Strategies aimed at targeting the stem-like AP pool could emerge as novel and powerful immunotherapeutic interventions for T1D.

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Affiliations

1. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

   Sofia V. Gearty, Gabriel Espinosa-Carrasco, Mojdeh Shakiba, Prerak Trivedi & Andrea Schietinger

2. Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA

   Sofia V. Gearty & Andrea Schietinger

3. Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA

   Friederike Dündar & Paul Zumbo

4. Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY, USA

   Friederike Dündar, Paul Zumbo & Doron Betel

5. Cancer Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

   Francisco J. Sanchez-Rivera & Scott W. Lowe

6. Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA

   Nicholas D. Socci

7. Aduro Biotech, Inc., Berkeley, CA, USA

   Peter Lauer

8. Integrated Genomics Operation Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA

   Neeman Mohibullah & Agnes Viale

9. Department of Microbiology and Immunology & Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

   Teresa P. DiLorenzo

10. Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Teresa P. DiLorenzo

11. The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY, USA

    Teresa P. DiLorenzo

12. Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA

    Doron Betel

13. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Doron Betel

Authors

1. Sofia V. Gearty
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2. Friederike Dündar
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3. Paul Zumbo
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4. Gabriel Espinosa-Carrasco
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5. Mojdeh Shakiba
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6. Francisco J. Sanchez-Rivera
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7. Nicholas D. Socci
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8. Prerak Trivedi
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9. Scott W. Lowe
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10. Peter Lauer
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11. Neeman Mohibullah
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12. Agnes Viale
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13. Teresa P. DiLorenzo
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14. Doron Betel
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15. Andrea Schietinger
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Corresponding authors

Correspondence to Doron Betel or Andrea Schietinger.

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Supplementary Figure 1

Representative flow cytometry gating strategies.

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Gearty, S.V., Dündar, F., Zumbo, P. et al. An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature (2021). https://ift.tt/2ZEYufH

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• Received: 20 July 2020

• Accepted: 15 November 2021

• Published: 30 November 2021

• DOI: https://doi.org/10.1038/s41586-021-04248-x

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