Global Activation of CD8+ Cytotoxic T Lymphocytes Correlates with an Impairment in Regulatory T Cells in Patients with Generalized Vitiligo

Abstract

Melanocyte-specific CD8+ cytotoxic T lymphocytes (CTLs) play a pivotal role in vitiligo-induced depigmentation. Yet, the mechanisms underlying the high frequency of generalized autoimmune disorders associated with generalized vitiligo (GV) are unknown. We hypothesized that an imbalance between activated CD8+ CTLs and regulatory T cells (Tregs) exists in patients with GV . Assessment of the circulating CD8+ CTLs and Tregs by flow cytometric analysis revealed an obvious expansion of CD8+ CTLs and a concomitant decrease in Treg cells in GV patients. The percentages of skin infiltrating CD8+ CTLs and Tregs were evaluated by immunohistochemistry and revealed dramatically increased numbers of both CD8+ CTLs and Tregs in the perilesional skin of GV patients. However, peripheral Tregs were impaired in their ability to suppress the proliferation and cytolytic capacity of autologous CD8+ T cells, suggesting that a functional failure of Tregs and the hyper-activation of CD8+ CTLs may contribute to progressive GV. Our data indicate that reduced numbers and impaired function of natural Tregs fail to control the widespread activation of CD8+ CTLs, which leads to the destruction of melanocytes and contributes to the elevated frequency of various associated autoimmune diseases. This knowledge furthers our understanding of the mechanisms of immune tolerance that are impaired in GV patients and may aid in the future development of effective immunotherapy for GV patients.

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

“…Such alterations might lead to the higher levels and activation of cytotoxic T cells (Fig. 1) which have been reported in individuals with the disease [10,11]. Currently, however, studies examining any reciprocal relationship between CD4 + CD25 + FoxP3 + Tregs and CD8 + in vitiligo progression are lacking.…”

“…More recently, repigmentation in a mouse model of spontaneous epidermal depigmentation was found to be accompanied by an increased Treg cell infiltration, suggesting their importance in preventing an ongoing immune response against melanocytes [17]. To date, several studies have indicated perturbations in Treg cell numbers and/or function in vitiligo patients [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Such alterations might lead to the higher levels and activation of cytotoxic T cells (Fig.…”

“…Several studies have been carried out to look for alterations in Treg cell numbers in vitiligo (Table 1) [10][11][12][13][14][15][16][17][18][19][20][21][22][23]26,27]. Assessment of circulating Tregs by flow cytometric analysis has revealed a decrease in their numbers in vitiligo patients compared to controls [10,11,13].…”

“…Assessment of circulating Tregs by flow cytometric analysis has revealed a decrease in their numbers in vitiligo patients compared to controls [10,11,13].…”

“…1). In addition, there is a global expansion and widespread activation of the CD8 + T cell population in vitiligo patients [10][11][12]. So far, however, the exact mechanisms underlying the induction and activation of autoreactive CD8 + T cells and the loss of tolerance to melanocyte autoantigens in vitiligo are not clear, but as with other autoimmune disorders, it seems likely that this loss of tolerance to self must involve some defect in regulatory T cell (Tregs) function [10,11,13].…”