Figure 2. Progression of vitiligo requires continued recruitment of T cells which occurs via a positive-feedback loop. In the progressive phase of vitiligo, melanocyte-reactive CD8+T cells produce interferon-gamma on encountering melanocyte antigens. These induce keratinocytes to secrete CXCL 9 and CXCL 10, resulting in additional recruitment of lymphocytes to the site through the CXCR3 receptor (Adapted from Frisoli et al., 2020)[39].
In a mouse model of vitiligo, repigmentation was accompanied by an elevated infiltration of Tregs into the skin, possibly resulting in the prevention of immune responses against melanocytes [79]. In addition, studies reported an increase in vitiligo severity when Treg cells were depleted using either CD4 or CD25 antibodies [80, 81]. One study showed an increase in cutaneous Treg cell infiltration and a decrease in depigmentation when the expression of CCL22 was induced in the skin [82]. Another report revealed that adoptive transfer of exogenous Treg cells vitiligo prone mice at three weeks of age led to elevated number of cutaneous Treg cells and prevented vitiligo [81].
When vitiligo prone mice were injected with PD-L1P-Fc, Treg cell accumulation in the skin was enhanced and depigmentation was reversed [83]. These findings support the theory that the number of Treg cells in skin is critical for reducing depigmentation driven by T effectors and therefore helping to control vitiligo progression.
Several groups have reported disruption of Treg cells function, but there is no consensus as to where the disruption exactly lies: in density of Treg cells, suppressive effects, or immigration ability to the skin. Studies reported that peripheral Treg cells isolated from vitiligo patients showed a decreased ability to inhibit CD8+ T cells proliferation and activation in vitro [84]. However, another study showed normal Treg cell activity in vitiligo patients but decreased number in the skin, suggesting that reduced cutaneous localization of Treg cells to the skin, rather than diminished function of Treg cells, contributes to vitiligo pathogenesis [85] . Immunohistochemical studies revealed no significant reduction in Treg cell number in vitiligo lesional skin [86, 87], whereas another report showed a significant decrease in these cells [88]. It is therefore not clear how the function of Treg is disrupted in vitiligo patients, but effector T cell phenotype in human vitiligo also indicates the presence of defective Treg T cells. Naturally occurring Treg cells reduce self-reactive T cell proliferation and activation, a phenomenon called anergy, and analysis of the phenotype of peripheral blood mononuclear cells indicates that melanocyte-autoreactive CD8+ T cells escape anergy in vitiligo patients [89]. Further studies are required to reliably determine how deficiency of Treg cells contributes to the development of vitiligo, and to examine the potential of improving Treg cell function as a novel treatment for vitiligo.