The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease

Cameron S McDonald-Hyman; James T. Muller; Michael Loschi; Govindarajan Thangavelu; Asim Saha; Sudha Kumari; Dawn K Reichenbach; Michelle J. Smith; Guoan Zhang; Brent Koehn; Jiqiang Lin; Jason S Mitchell; Brian T Fife; Angela Panoskaltsis-Mortari; Colby J Feser; Andrew Kemal Kirchmeier; Mark J Osborn; Keli L Hippen; Ameeta Kelekar; Jonathan S. Serody; Laurence A. Turka; David H. Munn; Hongbo Chi; Thomas A. Neubert; Michael L. Dustin; Bruce R Blazar

doi:10.1172/JCI95713

The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease

Cameron S McDonald-Hyman, James T. Muller, Michael Loschi, Govindarajan Thangavelu, Asim Saha, Sudha Kumari, Dawn K Reichenbach, Michelle J. Smith, Guoan Zhang, Brent Koehn, Jiqiang Lin, Jason S Mitchell, Brian T Fife, Angela Panoskaltsis-Mortari, Colby J Feser, Andrew Kemal Kirchmeier, Mark J Osborn, Keli L Hippen, Ameeta Kelekar, Jonathan S. SerodyLaurence A. Turka, David H. Munn, Hongbo Chi, Thomas A. Neubert, Michael L. Dustin, Bruce R Blazar

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

26 Scopus citations

Abstract

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.

Original language	English (US)
Pages (from-to)	4604-4621
Number of pages	18
Journal	Journal of Clinical Investigation
Volume	128
Issue number	10
DOIs	https://doi.org/10.1172/JCI95713
State	Published - Oct 1 2018

Bibliographical note

Funding Information:
The authors thank Amnon Altman (La Jolla Institute for Allergy and Immunology) for his commentary, David Bernlohr and Rocio Foncea (Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota), and the Minnesota Obesity Center for assistance with the Seahorse experiments. This work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), the National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute (NCI), the National Center for Research Resources (NCRR), the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH under grant numbers P01 AI056299, R01 HL56067, AI112613, AI34495, and P01 CA142106 (to BRB); R01 AI043542 (to MLD); T32 AI007313 and F30 HL121873 (to CMH); R01 AI106791 (to BTF); R01 CA157971 (to AK); R01 AI191497 and R01 AI105887 (to HC); S10 RR027990 (to TAN); S10 RR023704-01A1 (NYUSOM Microscopy Core); P30 DK050456 (MN Obesity center); and P01 AI056299 (to LAT). The Zeiss 710 MP microscope was purchased in part with funds from NIH grant RR023704-01A1. The Nikon TIRFM was purchased with funds from NIH grants P01AI080192 and R37AI043542. We thank M. Cammer for support with light microscopy and F. Liang for electron microscopy assistance through the NYULMC Office of Collaborative Science Microscopy Core.

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© 2018 American Society for Clinical Investigation. All rights reserved.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159973

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McDonald-Hyman, C. S., Muller, J. T., Loschi, M., Thangavelu, G., Saha, A., Kumari, S., Reichenbach, D. K., Smith, M. J., Zhang, G., Koehn, B., Lin, J., Mitchell, J. S., Fife, B. T., Panoskaltsis-Mortari, A., Feser, C. J., Kirchmeier, A. K., Osborn, M. J., Hippen, K. L., Kelekar, A., ... Blazar, B. R. (2018). The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease. Journal of Clinical Investigation, 128(10), 4604-4621. https://doi.org/10.1172/JCI95713

McDonald-Hyman, CS, Muller, JT, Loschi, M, Thangavelu, G, Saha, A, Kumari, S, Reichenbach, DK, Smith, MJ, Zhang, G, Koehn, B, Lin, J, Mitchell, JS, Fife, BT , Panoskaltsis-Mortari, A , Feser, CJ, Kirchmeier, AK, Osborn, MJ , Hippen, KL , Kelekar, A, Serody, JS, Turka, LA, Munn, DH, Chi, H, Neubert, TA, Dustin, ML & Blazar, BR 2018, 'The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease', Journal of Clinical Investigation, vol. 128, no. 10, pp. 4604-4621. https://doi.org/10.1172/JCI95713

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title = "The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease",

abstract = "Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.",

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note = "Funding Information: The authors thank Amnon Altman (La Jolla Institute for Allergy and Immunology) for his commentary, David Bernlohr and Rocio Foncea (Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota), and the Minnesota Obesity Center for assistance with the Seahorse experiments. This work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), the National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute (NCI), the National Center for Research Resources (NCRR), the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH under grant numbers P01 AI056299, R01 HL56067, AI112613, AI34495, and P01 CA142106 (to BRB); R01 AI043542 (to MLD); T32 AI007313 and F30 HL121873 (to CMH); R01 AI106791 (to BTF); R01 CA157971 (to AK); R01 AI191497 and R01 AI105887 (to HC); S10 RR027990 (to TAN); S10 RR023704-01A1 (NYUSOM Microscopy Core); P30 DK050456 (MN Obesity center); and P01 AI056299 (to LAT). The Zeiss 710 MP microscope was purchased in part with funds from NIH grant RR023704-01A1. The Nikon TIRFM was purchased with funds from NIH grants P01AI080192 and R37AI043542. We thank M. Cammer for support with light microscopy and F. Liang for electron microscopy assistance through the NYULMC Office of Collaborative Science Microscopy Core. Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Investigation. All rights reserved.",

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T1 - The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease

AU - McDonald-Hyman, Cameron S

AU - Muller, James T.

AU - Loschi, Michael

AU - Thangavelu, Govindarajan

AU - Saha, Asim

AU - Kumari, Sudha

AU - Reichenbach, Dawn K

AU - Smith, Michelle J.

AU - Zhang, Guoan

AU - Koehn, Brent

AU - Lin, Jiqiang

AU - Mitchell, Jason S

AU - Fife, Brian T

AU - Panoskaltsis-Mortari, Angela

AU - Feser, Colby J

AU - Kirchmeier, Andrew Kemal

AU - Osborn, Mark J

AU - Hippen, Keli L

AU - Kelekar, Ameeta

AU - Serody, Jonathan S.

AU - Turka, Laurence A.

AU - Munn, David H.

AU - Chi, Hongbo

AU - Neubert, Thomas A.

AU - Dustin, Michael L.

AU - Blazar, Bruce R

N1 - Funding Information: The authors thank Amnon Altman (La Jolla Institute for Allergy and Immunology) for his commentary, David Bernlohr and Rocio Foncea (Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota), and the Minnesota Obesity Center for assistance with the Seahorse experiments. This work was funded by the National Institute of Allergy and Infectious Diseases (NIAID), the National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute (NCI), the National Center for Research Resources (NCRR), the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH under grant numbers P01 AI056299, R01 HL56067, AI112613, AI34495, and P01 CA142106 (to BRB); R01 AI043542 (to MLD); T32 AI007313 and F30 HL121873 (to CMH); R01 AI106791 (to BTF); R01 CA157971 (to AK); R01 AI191497 and R01 AI105887 (to HC); S10 RR027990 (to TAN); S10 RR023704-01A1 (NYUSOM Microscopy Core); P30 DK050456 (MN Obesity center); and P01 AI056299 (to LAT). The Zeiss 710 MP microscope was purchased in part with funds from NIH grant RR023704-01A1. The Nikon TIRFM was purchased with funds from NIH grants P01AI080192 and R37AI043542. We thank M. Cammer for support with light microscopy and F. Liang for electron microscopy assistance through the NYULMC Office of Collaborative Science Microscopy Core. Publisher Copyright: © 2018 American Society for Clinical Investigation. All rights reserved.

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Y1 - 2018/10/1

N2 - Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.

AB - Regulatory T cells (Tregs) are critical for maintaining immune homeostasis. However, current Treg immunotherapies do not optimally treat inflammatory diseases in patients. Understanding the cellular processes that control Treg function may allow for the augmentation of therapeutic efficacy. In contrast to activated conventional T cells, in which protein kinase C-θ (PKC-θ) localizes to the contact point between T cells and antigen-presenting cells, in human and mouse Tregs, PKC-θ localizes to the opposite end of the cell in the distal pole complex (DPC). Here, using a phosphoproteomic screen, we identified the intermediate filament vimentin as a PKC-θ phospho target and show that vimentin forms a DPC superstructure on which PKC-θ accumulates. Treatment of mouse Tregs with either a clinically relevant PKC-θ inhibitor or vimentin siRNA disrupted vimentin and enhanced Treg metabolic and suppressive activity. Moreover, vimentin-disrupted mouse Tregs were significantly better than controls at suppressing alloreactive T cell priming in graft-versus-host disease (GVHD) and GVHD lethality, using a complete MHC-mismatch mouse model of acute GVHD (C57BL/6 donor into BALB/c host). Interestingly, vimentin disruption augmented the suppressor function of PKC-θ-deficient mouse Tregs. This suggests that enhanced Treg activity after PKC-θ inhibition is secondary to effects on vimentin, not just PKC-θ kinase activity inhibition. Our data demonstrate that vimentin is a key metabolic and functional controller of Treg activity and provide proof of principle that disruption of vimentin is a feasible, translationally relevant method to enhance Treg potency.

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The vimentin intermediate filament network restrains regulatory T cell suppression of graft-versus-host disease

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