Antigen Specificity Enhances Disease Control by Tregs in Vitiligo

Zhussipbek Mukhatayev; Emilia R. Dellacecca; Cormac Cosgrove; Rohan Shivde; Dinesh Jaishankar; Katherine Pontarolo-Maag; Jonathan M. Eby; Steven W. Henning; Yekaterina O. Ostapchuk; Kettil Cedercreutz; Alpamys Issanov; Shikhar Mehrotra; Andreas Overbeck; Richard P. Junghans; Joseph R. Leventhal; I. Caroline Le Poole

doi:10.3389/fimmu.2020.581433

Antigen Specificity Enhances Disease Control by Tregs in Vitiligo

Zhussipbek Mukhatayev^*, Emilia R. Dellacecca, Cormac Cosgrove, Rohan Shivde, Dinesh Jaishankar, Katherine Pontarolo-Maag, Jonathan M. Eby, Steven W. Henning, Yekaterina O. Ostapchuk, Kettil Cedercreutz, Alpamys Issanov, Shikhar Mehrotra, Andreas Overbeck, Richard P. Junghans, Joseph R. Leventhal, I. Caroline Le Poole

^*Corresponding author for this work

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

52 Scopus citations

Abstract

Vitiligo is an autoimmune skin disease characterized by melanocyte destruction. Regulatory T cells (Tregs) are greatly reduced in vitiligo skin, and replenishing peripheral skin Tregs can provide protection against depigmentation. Ganglioside D3 (GD3) is overexpressed by perilesional epidermal cells, including melanocytes, which prompted us to generate GD3-reactive chimeric antigen receptor (CAR) Tregs to treat vitiligo. Mice received either untransduced Tregs or GD3-specific Tregs to test the hypothesis that antigen specificity contributes to reduced autoimmune reactivity in vitro and in vivo. CAR Tregs displayed increased IL-10 secretion in response to antigen, provided superior control of cytotoxicity towards melanocytes, and supported a significant delay in depigmentation compared to untransduced Tregs and vehicle control recipients in a TCR transgenic mouse model of spontaneous vitiligo. The latter findings were associated with a greater abundance of Tregs and melanocytes in treated mice versus both control groups. Our data support the concept that antigen-specific Tregs can be prepared, used, and stored for long-term control of progressive depigmentation.

Original language	English (US)
Article number	581433
Journal	Frontiers in immunology
Volume	11
DOIs	https://doi.org/10.3389/fimmu.2020.581433
State	Published - Dec 1 2020

Funding

This study was supported in part by NIH RO1s AR057643, CA191317, and by The LAM Foundation through an Established Investigator award to CLP. A foreign internship to ZM was supported by the Ministry of Education and Science of the Republic of Kazakhstan under the Ph.D. program at Al-Farabi Kazakh National University. We kindly acknowledge NCI Biological Resources Branch for providing rhIL-2 used for in vivo studies. We greatly appreciate the patients who provide informed consent to use the skin tissues for the study, and Northwestern University Skin Biology and Diseases Resource-Based Center (SBDRC) TEST IT core for the technical assistance.

Keywords

antigen-specific Treg
autoimmune diseases
chimeric antigen receptor T cells
ganglioside D3
regulatory T cells
vitiligo

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.3389/fimmu.2020.581433

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Mukhatayev, Z., Dellacecca, E. R., Cosgrove, C., Shivde, R., Jaishankar, D., Pontarolo-Maag, K., Eby, J. M., Henning, S. W., Ostapchuk, Y. O., Cedercreutz, K., Issanov, A., Mehrotra, S., Overbeck, A., Junghans, R. P., Leventhal, J. R., & Le Poole, I. C. (2020). Antigen Specificity Enhances Disease Control by Tregs in Vitiligo. Frontiers in immunology, 11, Article 581433. https://doi.org/10.3389/fimmu.2020.581433

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title = "Antigen Specificity Enhances Disease Control by Tregs in Vitiligo",

abstract = "Vitiligo is an autoimmune skin disease characterized by melanocyte destruction. Regulatory T cells (Tregs) are greatly reduced in vitiligo skin, and replenishing peripheral skin Tregs can provide protection against depigmentation. Ganglioside D3 (GD3) is overexpressed by perilesional epidermal cells, including melanocytes, which prompted us to generate GD3-reactive chimeric antigen receptor (CAR) Tregs to treat vitiligo. Mice received either untransduced Tregs or GD3-specific Tregs to test the hypothesis that antigen specificity contributes to reduced autoimmune reactivity in vitro and in vivo. CAR Tregs displayed increased IL-10 secretion in response to antigen, provided superior control of cytotoxicity towards melanocytes, and supported a significant delay in depigmentation compared to untransduced Tregs and vehicle control recipients in a TCR transgenic mouse model of spontaneous vitiligo. The latter findings were associated with a greater abundance of Tregs and melanocytes in treated mice versus both control groups. Our data support the concept that antigen-specific Tregs can be prepared, used, and stored for long-term control of progressive depigmentation.",

keywords = "antigen-specific Treg, autoimmune diseases, chimeric antigen receptor T cells, ganglioside D3, regulatory T cells, vitiligo",

author = "Zhussipbek Mukhatayev and Dellacecca, {Emilia R.} and Cormac Cosgrove and Rohan Shivde and Dinesh Jaishankar and Katherine Pontarolo-Maag and Eby, {Jonathan M.} and Henning, {Steven W.} and Ostapchuk, {Yekaterina O.} and Kettil Cedercreutz and Alpamys Issanov and Shikhar Mehrotra and Andreas Overbeck and Junghans, {Richard P.} and Leventhal, {Joseph R.} and {Le Poole}, {I. Caroline}",

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Mukhatayev, Dellacecca, Cosgrove, Shivde, Jaishankar, Pontarolo-Maag, Eby, Henning, Ostapchuk, Cedercreutz, Issanov, Mehrotra, Overbeck, Junghans, Leventhal and Le Poole.",

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Mukhatayev, Z, Dellacecca, ER, Cosgrove, C, Shivde, R, Jaishankar, D, Pontarolo-Maag, K, Eby, JM, Henning, SW, Ostapchuk, YO, Cedercreutz, K, Issanov, A, Mehrotra, S, Overbeck, A, Junghans, RP, Leventhal, JR & Le Poole, IC 2020, 'Antigen Specificity Enhances Disease Control by Tregs in Vitiligo', Frontiers in immunology, vol. 11, 581433. https://doi.org/10.3389/fimmu.2020.581433

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T1 - Antigen Specificity Enhances Disease Control by Tregs in Vitiligo

AU - Mukhatayev, Zhussipbek

AU - Dellacecca, Emilia R.

AU - Cosgrove, Cormac

AU - Shivde, Rohan

AU - Jaishankar, Dinesh

AU - Pontarolo-Maag, Katherine

AU - Eby, Jonathan M.

AU - Henning, Steven W.

AU - Ostapchuk, Yekaterina O.

AU - Cedercreutz, Kettil

AU - Issanov, Alpamys

AU - Mehrotra, Shikhar

AU - Overbeck, Andreas

AU - Junghans, Richard P.

AU - Leventhal, Joseph R.

AU - Le Poole, I. Caroline

N1 - Publisher Copyright: © Copyright © 2020 Mukhatayev, Dellacecca, Cosgrove, Shivde, Jaishankar, Pontarolo-Maag, Eby, Henning, Ostapchuk, Cedercreutz, Issanov, Mehrotra, Overbeck, Junghans, Leventhal and Le Poole.

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N2 - Vitiligo is an autoimmune skin disease characterized by melanocyte destruction. Regulatory T cells (Tregs) are greatly reduced in vitiligo skin, and replenishing peripheral skin Tregs can provide protection against depigmentation. Ganglioside D3 (GD3) is overexpressed by perilesional epidermal cells, including melanocytes, which prompted us to generate GD3-reactive chimeric antigen receptor (CAR) Tregs to treat vitiligo. Mice received either untransduced Tregs or GD3-specific Tregs to test the hypothesis that antigen specificity contributes to reduced autoimmune reactivity in vitro and in vivo. CAR Tregs displayed increased IL-10 secretion in response to antigen, provided superior control of cytotoxicity towards melanocytes, and supported a significant delay in depigmentation compared to untransduced Tregs and vehicle control recipients in a TCR transgenic mouse model of spontaneous vitiligo. The latter findings were associated with a greater abundance of Tregs and melanocytes in treated mice versus both control groups. Our data support the concept that antigen-specific Tregs can be prepared, used, and stored for long-term control of progressive depigmentation.

AB - Vitiligo is an autoimmune skin disease characterized by melanocyte destruction. Regulatory T cells (Tregs) are greatly reduced in vitiligo skin, and replenishing peripheral skin Tregs can provide protection against depigmentation. Ganglioside D3 (GD3) is overexpressed by perilesional epidermal cells, including melanocytes, which prompted us to generate GD3-reactive chimeric antigen receptor (CAR) Tregs to treat vitiligo. Mice received either untransduced Tregs or GD3-specific Tregs to test the hypothesis that antigen specificity contributes to reduced autoimmune reactivity in vitro and in vivo. CAR Tregs displayed increased IL-10 secretion in response to antigen, provided superior control of cytotoxicity towards melanocytes, and supported a significant delay in depigmentation compared to untransduced Tregs and vehicle control recipients in a TCR transgenic mouse model of spontaneous vitiligo. The latter findings were associated with a greater abundance of Tregs and melanocytes in treated mice versus both control groups. Our data support the concept that antigen-specific Tregs can be prepared, used, and stored for long-term control of progressive depigmentation.

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KW - chimeric antigen receptor T cells

KW - ganglioside D3

KW - regulatory T cells

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Antigen Specificity Enhances Disease Control by Tregs in Vitiligo

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