IFN-γ Signaling Pathway Acts as a Key Driver of CD8+ T Cell
Recruitment and Function in Vitiligo
The mechanism by which CD8+ T cells trigger melanocytes apoptosis
requires their secretion of proinflammatory cytokines IFN-γ from CD8+ T
cells [68]. Analysis of gene expression in human vitiligo lesional
skin demonstrated increased expression of IFRG gene [70, 71],
as well as genes induced by IFN-γ and these include C-X-C chemokine
receptor type 3 (CXCR3) , a T cell chemokine receptor, and its
ligands: CXCL9 , CXCL10 , and CXCL11 [71]. In
agreement with this finding, skin biopsies from vitiligo patient lesions
also show prominent lymphocyte infiltrates that are primarily CXCR3+
[69, 71-73]. In addition, melanocyte-specific CD8+ T cells isolated
from the skin and blood vitiligo subjects predominantly express CXCR3
receptor, and CXCL9 is a specific skin biomarker of active vitiligo
[65]. Studies in mouse models of vitiligo established a critical
role for pathway in pathogenesis of vitiligo, since INF-γ, CXCR3, CXCL10
are all essential for vitiligo development [71, 74]. Neutralization
of IFN-γ with antibody treatment or the lack of CXCR3 expression
on T cells prevents the migration of autoreactive T cells into the skin
and therefore do not cause depigmentation [71, 74]. Studies
employing chemokine reporter mice showed that CXCL9 and CXCL10 are
mostly produced by keratinocytes, and functional studies demonstrated
that keratinocytes are primarily responsible for recruitment of
autoreactive T cells [75].
CXCL9 seems predominantly responsible for bulk recruitment of T cells to
the skin, since when it is absent the number of melanocyte autoreactive
T cells within lesional skin of vitiligo is decreased by tenfold
[71]. However, in spite of reduced number of T cells, vitiligo
severity remains unchanged, indicating that the over-recruitment of T
cells occurs during vitiligo. In contrast, when CXCL10 is absent, the
incidence and severity of vitiligo are decreased, yet bulk recruitment
of T cells is unchanged [71].
Interestingly, in the absence of CXCL10, the quantity of T cells shown
in the epidermis compared to the dermis in the skin is decreased,
signifying that CXCL10 is responsible for T cell localisation within the
skin and their effector function [71]. Thus, T cells produces IFN-γ,
which stimulates the production of CXCL9 and CXCL10 from keratinocytes
to recruit more T cells and induce vitiligo progression [39]. As
well as to vitiligo initiation and progression, the IFN-γ-chemokine
pathway is also needed for maintenance of established vitiligo lesions,
as knocking out CXCR3 or blocking CXCL10 action prevents and reverses
depigmentation in vitiligo [71] (Figure 2) . Indeed,
ruxolitinib, a janus kinase (JAK)-1,2 inhibitor, which interferes with
IFN-γ signalling pathway through preferential inhibition of JAK1 and
JAK2, shows promise in vitiligo [76].