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.