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].