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Modulation of PKM Activity Controls Differentiation of Th17 Cells

29 Pages Posted: 2 Apr 2019 Publication Status: Review Complete

See all articles by Scott M. Seki

Scott M. Seki

University of Virginia - Center for Brain Immunology and Glia; University of Virginia - Graduate Program in Neuroscience; University of Virginia - Medical Scientist Training Program

Kacper Posyniak

University of Virginia - Center for Brain Immunology and Glia

Rebecca McCloud

University of Virginia - Department of Microbiology, Immunology and Cancer Biology; University of Virginia - Department of Chemistry

Dorian A. Rosen

University of Virginia - Center for Brain Immunology and Glia

Anthony Fernandez-Castaneda

University of Virginia - Center for Brain Immunology and Glia

Rebecca M. Beiter

University of Virginia - Center for Brain Immunology and Glia

Nikolas Hayes

University of Virginia - Center for Brain Immunology and Glia

Charles Spivey

University of Virginia - Center for Brain Immunology and Glia

Lelisa Gemta

University of Virginia - Department of Pathology

Timothy N.J. Bullock

University of Virginia - Department of Pathology

Ku-Lung Hsu

University of Virginia - Department of Microbiology, Immunology and Cancer Biology; University of Virginia - Department of Chemistry

Alban Gaultier

University of Virginia - Center for Brain Immunology and Glia

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Abstract

T cells play crucial, and perhaps initiating roles in autoimmune diseases like Multiple Sclerosis (MS). Elucidating the mechanisms that regulate inflammatory T cell responses could reveal novel means of modulation of their pathological role. Small molecules that target specific functions of the pyruvate kinase isoform PKM2, TEPP-46 and DASA-58, have gained attention as potential inhibitors of inflammation. Here, we assessed the therapeutic potential of both molecules in a preclinical mouse model of MS. We found that both compounds suppress the development of IL-17 producing T cells (Th17). However, while TEPP-46 and DASA-58 potently inhibited Th17 cell production of IL-17A, they unexpectedly boosted their GM-CSF production. This surprising switch redirected the disease pathology from the spinal cord to the brain. On a mechanistic level, we found that modulation of PKM2 interferes with TGFβ1 signaling needed for the development of Th17 and regulatory T cells. Collectively, our study addresses a major outstanding question regarding the therapeutic potential of PKM2 modulation in MS and contributes new information to the mechanistic basis of such modulation on T cell functions.

Keywords: PKM, T cells, multiple sclerosis, Metabolism, GMCSF, IL-17

Suggested Citation

Seki, Scott M. and Posyniak, Kacper and McCloud, Rebecca and Rosen, Dorian A. and Fernandez-Castaneda, Anthony and Beiter, Rebecca M. and Hayes, Nikolas and Spivey, Charles and Gemta, Lelisa and Bullock, Timothy N.J. and Hsu, Ku-Lung and Gaultier, Alban, Modulation of PKM Activity Controls Differentiation of Th17 Cells (April 1, 2019). Available at SSRN: https://ssrn.com/abstract=3363732 or http://dx.doi.org/10.2139/ssrn.3363732
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Scott M. Seki

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

University of Virginia - Graduate Program in Neuroscience

1400 University Ave
Charlottesville, VA 22903
United States

University of Virginia - Medical Scientist Training Program

1400 University Ave
Charlottesville, VA 22903
United States

Kacper Posyniak

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

Rebecca McCloud

University of Virginia - Department of Microbiology, Immunology and Cancer Biology

1400 University Ave
Charlottesville, VA 22903
United States

University of Virginia - Department of Chemistry

1400 University Ave
Charlottesville, VA 22903
United States

Dorian A. Rosen

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

Anthony Fernandez-Castaneda

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

Rebecca M. Beiter

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

Nikolas Hayes

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

Charles Spivey

University of Virginia - Center for Brain Immunology and Glia

1400 University Ave
Charlottesville, VA 22903
United States

Lelisa Gemta

University of Virginia - Department of Pathology

1400 University Ave
Charlottesville, VA 22903
United States

Timothy N.J. Bullock

University of Virginia - Department of Pathology

1400 University Ave
Charlottesville, VA 22903
United States

Ku-Lung Hsu

University of Virginia - Department of Microbiology, Immunology and Cancer Biology

1400 University Ave
Charlottesville, VA 22903
United States

University of Virginia - Department of Chemistry

1400 University Ave
Charlottesville, VA 22903
United States

Alban Gaultier (Contact Author)

University of Virginia - Center for Brain Immunology and Glia ( email )

1400 University Ave
Charlottesville, VA 22903
United States

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