TY - JOUR
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 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© Copyright © 2020 Mukhatayev, Dellacecca, Cosgrove, Shivde, Jaishankar, Pontarolo-Maag, Eby, Henning, Ostapchuk, Cedercreutz, Issanov, Mehrotra, Overbeck, Junghans, Leventhal and Le Poole.
PY - 2020/12/1
Y1 - 2020/12/1
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.
KW - antigen-specific Treg
KW - autoimmune diseases
KW - chimeric antigen receptor T cells
KW - ganglioside D3
KW - regulatory T cells
KW - vitiligo
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U2 - 10.3389/fimmu.2020.581433
DO - 10.3389/fimmu.2020.581433
M3 - Article
C2 - 33335528
AN - SCOPUS:85097612179
SN - 1664-3224
VL - 11
SP - 581433
JO - Frontiers in Immunology
JF - Frontiers in Immunology
ER -