Antigen Specificity Enhances Disease Control by Tregs in Vitiligo.

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

doi:10.3389/fimmu.2020.581433

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.

Highlights

Vitiligo is an autoimmune disease wherein melanocytes are progressively destroyed, resulting in pale, white patches of skin [1, 2]
Ganglioside D3 (GD3) Is Expressed by Perilesional Epithelial Cells Including Melanocytes
Overexpression of O-acetylated GD3 has been reported for actively depigmenting vitiligo skin [31, 38]

Summary

Introduction

Vitiligo is an autoimmune disease wherein melanocytes are progressively destroyed, resulting in pale, white patches of skin [1, 2]. HSP70i can directly activate innate immune cells and Antigen-Specific Tregs Control Vitiligo chaperone melanocyte antigens for subsequent introduction to antigen presenting cells (APCs) [8, 9]. These innate immune cells and APCs recruit auto-reactive T cells to mediate specific destruction of melanocytes in vitiligo [10]. Tregs are subsets of T cells responsible for peripheral tolerance via suppression of immune cells, including self-reactive, cytotoxic T cells, to maintain immune homeostasis [13]. Limited Treg activity in vitiligo skin allows autoreactive, cytotoxic T cells to expand and eliminate melanocytes from the skin, facilitating progressive depigmentation [12]

Objectives

Methods

Results

Conclusion