Involvement of CXCR3 expressing effector memory skin T cells in the autoimmune pathogenesis of vitiligo – VIEMTEC

Vitiligo is the most common skin depigmenting disorder, affecting 1% of the general population. This stigmatizing disease has major social and psychological impact with significant unmet treatment needs. However, despite its prevalence, no specific effective intervention has been reported so far. Vitiligo is clinically characterized by symmetric and bilateral white macules, resulting from a loss of epidermal melanocytes, the pigment-producing cells. Several mechanisms have been implicated to explain melanocyte disappearance, including genetic predisposition, environmental triggers (such as friction), metabolic alteration, and altered inflammatory and immune responses.

The auto-immune and inflammatory theory is the leading hypothesis, based on the fact that 1/ vitiligo is often associated with autoimmune diseases (e.g. autoimmune thyroiditis, type I diabetes); 2/ genome-wide association studies and functional pathway analyses have shown that most vitiligo susceptibility loci encode components of the immune system; and 3/ prominent infiltration of plasmacytoïd dendritic cells (pDC), cytotoxic CD8+ T cells together with CD4+ T cells is found in proximity to vitiligo lesional skin (perilesional skin). We have previously demonstrated a major role for interferon (IFN)-alpha, mainly produced by pDC, which induces an adaptive T cell response characterized by the recruitment and activation of Th1 and Tc1 cells expressing CXCR3 and producing elevated levels of IFN-gamma and tumor necrosis factor (TNF)-alpha. These two inflammatory cytokines act on melanocytes to induce their loss. Furthermore, the expression of the CXCR3 ligands, CXCL9 and CXCL10, is increased in the skin of vitiligo patients with active disease. However, the role of the CXCR3/CXCL9-10 axis in the immune response leading to vitiligo remains elusive.

The aim of our project is to decipher the role of the CXCR3/CXCL9-10 axis during vitiligo progression. Both human and mouse studies will be performed to determine whether targeting CXCR3 or its ligands could represent a new therapeutic target in this autoimmune disease. To this end, we will analyze the phenotype, function, and antigen specificity of skin CD4+ and CD8+ effector memory T cells expressing CXCR3 in vitiligo patients, and characterize their role within the epidermal environment (keratinocytes-melanocytes), which produces CXCL9 and CXCL10. The signaling pathways induced downstream of the CXCR3/CXCL9-10 axis will also be studied. Our results will be confirmed using mouse models and targeted therapies will be tested.

Altogether, this proposal will enable the characterization of the role of Th1 and Tc1 effector memory T cells expressing CXCR3 in melanocyte loss, locally in the skin, and to identify new therapeutic strategies targeting CXCR3, its ligands, or the signaling pathways induced in vitiligo.