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T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk

View ORCID ProfileDimitre R. Simeonov, View ORCID ProfileHarikesh S. Wong, Jessica T. Cortez, View ORCID ProfileArabella Young, Zhongmei Li, Vinh Nguyen, View ORCID ProfileKyemyung Park, Jennifer Umhoefer, Alyssa C. Indart, Jonathan M. Woo, Mark S. Anderson, View ORCID ProfileRonald N. Germain, View ORCID ProfileAlexander Marson
doi: https://doi.org/10.1101/2020.07.22.216564
Dimitre R. Simeonov
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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  • ORCID record for Dimitre R. Simeonov
  • For correspondence: dimitre.simeonov@ucsf.edu harikesh.wong@nih.gov rgermain@niaid.nih.gov alexander.marson@ucsf.edu
Harikesh S. Wong
4Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA
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  • For correspondence: dimitre.simeonov@ucsf.edu harikesh.wong@nih.gov rgermain@niaid.nih.gov alexander.marson@ucsf.edu
Jessica T. Cortez
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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Arabella Young
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
5QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
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Zhongmei Li
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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Vinh Nguyen
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
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Kyemyung Park
6Multiscale Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA
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Jennifer Umhoefer
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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Alyssa C. Indart
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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Jonathan M. Woo
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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Mark S. Anderson
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
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Ronald N. Germain
4Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA
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  • For correspondence: dimitre.simeonov@ucsf.edu harikesh.wong@nih.gov rgermain@niaid.nih.gov alexander.marson@ucsf.edu
Alexander Marson
1Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
2Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA
3Diabetes Center, University of California, San Francisco, CA 94143, USA
5QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia
7Department of Medicine, University of California, San Francisco, CA 94143, USA
8Gladstone Institutes, San Francisco, CA 94158, USA
9Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA
10Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
11Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
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  • ORCID record for Alexander Marson
  • For correspondence: dimitre.simeonov@ucsf.edu harikesh.wong@nih.gov rgermain@niaid.nih.gov alexander.marson@ucsf.edu
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Abstract

The majority of genetic variants associated with complex human autoimmune diseases reside in enhancers1–3, non-coding regulatory elements that control gene expression. In contrast with variants that directly alter protein-coding sequences, enhancer variants are predicted to tune gene expression modestly and function in specific cellular contexts4, suggesting that small alterations in the functions of key immune cell populations are sufficient to shape disease risk. Here we tested this concept by experimentally perturbing distinct enhancers governing the high affinity IL-2 receptor alpha chain (IL2RA; also known as CD25). IL2RA is an immune regulator that promotes the pro- and anti-inflammatory functions of conventional T cells (Tconvs) and regulatory T cells (Tregs), respectively, and non-coding genetic variants in IL2RA have been linked to multiple autoimmune disorders4. We previously tiled across the IL2RA locus using CRISPR-activation and identified a stimulation-responsive element (CaRE4) with an enhancer that modestly affects the kinetics of IL2RA expression in Tconvs5. This enhancer is conserved across species and harbors a common human SNP associated with protection from Type 1 Diabetes (T1D)5,6. We now identified an additional conserved enhancer, termed CaRE3 enhancer, which modestly affected steady state IL2RA expression in regulatory T cells (Tregs). Despite their seemingly subtle impact on gene expression, the CaRE3 and CaRE4 enhancers had pronounced yet divergent effects on the incidence of diabetes in autoimmune prone animals. Deletion of the conserved CaRE4 enhancer completely protected against autoimmune diabetes even in animals treated with an immunostimulating anti-PD1 checkpoint inhibitor, whereas deletion of the CaRE3 enhancer accelerated spontaneous disease progression. Quantitative multiplexed imaging of the pancreatic lymph nodes (panLNs) revealed that each enhancer deletion preferentially affected the protein expression levels of IL2RA in activated Tconvs or Tregs, reciprocally tuning local competition for IL-2 input signals. In animals lacking the CaRE4 enhancer, skewed IL-2 signaling favored Tregs, increasing their local density around activated Tconvs to strongly suppress emergence of autoimmune effectors. By contrast, in animals lacking the CaRE3 enhancer, IL-2 signals were skewed towards activated Tconvs, promoting their escape from Treg control. Collectively, this work illustrates how subtle changes in gene regulation due to non-coding variation can significantly alter disease progression and how distinct enhancers controlling the same gene can have opposing effects on disease outcomes through cell type-selective activity.

Competing Interest Statement

A.M. is a cofounder, member of the Boards of Directors and a member of the Scientific Advisory Boards of Spotlight Therapeutics and Arsenal Biosciences. A.M. has served as an advisor to Juno Therapeutics, was a member of the scientific advisory board at PACT Pharma, and was an advisor to Trizell. A.M. owns stock in Arsenal Biosciences, Spotlight Therapeutics and PACT Pharma. The Marson lab has received sponsored research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline and gifts from Gilead and Anthem. D.R.S. is a cofounder of Beeline Therapeutics.

Footnotes

  • ↵† Co-supervised this work

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk
Dimitre R. Simeonov, Harikesh S. Wong, Jessica T. Cortez, Arabella Young, Zhongmei Li, Vinh Nguyen, Kyemyung Park, Jennifer Umhoefer, Alyssa C. Indart, Jonathan M. Woo, Mark S. Anderson, Ronald N. Germain, Alexander Marson
bioRxiv 2020.07.22.216564; doi: https://doi.org/10.1101/2020.07.22.216564
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T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk
Dimitre R. Simeonov, Harikesh S. Wong, Jessica T. Cortez, Arabella Young, Zhongmei Li, Vinh Nguyen, Kyemyung Park, Jennifer Umhoefer, Alyssa C. Indart, Jonathan M. Woo, Mark S. Anderson, Ronald N. Germain, Alexander Marson
bioRxiv 2020.07.22.216564; doi: https://doi.org/10.1101/2020.07.22.216564

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