Figure 1. Activated NLRP3 inflammasome in keratinocytes promotes T cell responses in vitiligo. NLRP3 inflammasome in stressed keratinocytes is activated by NF-kB-mediated signaling as well as the interaction between mtROS and of NLRP3. NLRP3 inflammasome can also be activated through TRPM2-mediated intracellular and mitochondrial calcium influx. Once activated, NLRP3 inflammasome mediates caspase-1 cleavage which provoke synthesis of IL-β, resulting in the activation of D8+ and CD4+ T cells through IL1-β/IL-1R signaling pathway. IL1-β augments CXCR6 and CXCR3 expression in CD8+ T cells, IL17A/F synthesis in CD4+ T cells and IFN-γ production in both CD8+ and CD4+ T cells. IL1-β also promotes the expression of CXCL10 and CXCL16. TRPM2-facilitated NLRP3 inflammasome activation in keratinocytes stimulates T-cell function in vitiligo patients as demonstrated by upregulation of T cell activation markers CD69 and CD137 (Adapted from Li et al., 2020)[55].
Furthermore, perilesional infiltrating self-reactive CD8+ T cells in vitiligo patients recognise Melan-A/MART, tyrosinase (TYR) and melanocyte-specific protein, all of which are antigens involved in the melanogenic pathway [66].
Vitiligo patients showed elevated numbers of CD8+ T cells in their blood compared to healthy individuals [64].
Moreover, peri-lesional skin of vitiligo patients are highly infiltrated by melanocyte-specific CD8+ T cells [62], and these cells have the ability to kill melanocytes in vitro [62, 67, 68]. CD8+ T cells isolated from peri-lesional skin of vitiligo patients infiltrate explants of autologous healthy pigmented vitiligo skin and eliminate melanocytes in a way similar to the clinical pathology of vitiligo [68]. Importantly, isolated CD4+ T cells were incapable of inducing melanocyte apoptosis in autologous skin explants [68]. In vitro culture of CD8+ and CD4+ T cells derived from peri-lesional vitiligo skin secrete high levels interferon-γ (IFN-γ), a pro-inflammatory cytokine required for melanocyte-specific autoreactive CD8+ T cell recruitment [69]. These findings provide robust evidence that CD8+ T cells are equally essential and sufficient for destruction of melanocytes in vitiligo lesions.