Vitiligo Skin Is Imprinted with Resident Memory CD8 T Cells Expressing CXCR3

Abstract

Vitiligo is a chronic autoimmune depigmenting skin disorder that results from a loss of melanocytes. Multiple combinatorial factors have been involved in disease development, with a prominent role of the immune system, in particular T cells. After repigmentation, vitiligo frequently recurs in the same area, suggesting that vitiligo could involve the presence of resident memory T cells (T). We sought to perform a thorough characterization of the phenotype and function of skin memory T cells in vitiligo. We show that stable and active vitiligo perilesional skin is enriched with a population of CD8 T expressing both CD69 and CD103 compared with psoriasis and control unaffected skin. CD8 T expressing CD103 are mainly localized in the epidermis. Expression of CXCR3 is observed on most CD8 T in vitiligo, including the population of melanocyte-specific CD8 T cells. CD8 T displayed increased production of IFN-γ and tumor necrosis factor-α with moderate cytotoxic activity. Our study highlights the presence of functional CD8 T in both stable and active vitiligo, reinforcing the concept of vitiligo as an immune memory skin disease. The CD8 T that remain in stable disease could play a role during disease flares, emphasizing the interest in targeting this cell subset in vitiligo.

Vitiligo as a skin memory disease: The need for early intervention with immunomodulating agents and a maintenance therapy to target resident memory T cells

“…Indeed, increased oxidative stress, characterizing the disease, could lead to apoptosis of epidermal cells (keratinocytes and/or melanocytes) and subsequently to the release of self‐antigens that could induce in a predisposed patient response of the immune system with accumulation overtime of melanocytes specific T RM cells (Figure ). Accumulation of T RM in perilesional skin of patients with stable disease emphasize this concept and their involvement during reactivation of the disease. This could occur during repetitive flares up of the disease, leading to the recruitment of new populations of skin T RM not only at site of the flare‐up but all over the rest of the body.…”

“…We recently identified subsets of CD69 + CD103 + and CD69 + CD103 ‐ T RM that accumulate both in the epidermis and the dermis of perilesional skin of vitiligo patients with stable or active disease, CD103 + T RM being more abundant within the epidermis. Melanocyte‐specific T RM are characterized by the expression of CXCR3 and mount under activation high levels of the pro‐inflammatory cytokines TNFα and interferon IFNγ . T RM expressing CD49a were also observed both in the dermis and epidermis of vitiligo lesional skin and were characterized by production of IFNγ, perforin and granzyme B, notably when T RM cells were cultured in the presence of IL‐15, a cytokine that has been shown to be involved in T RM differentiation and maintenance.…”

“…Indeed, TNFα or IFNγ have been previously shown to inhibit melanocyte function, among other inflammatory cytokines . Regulatory T cells (Treg) dysfunction has also been previously reported in vitiligo skin and their replenishment could be of interest to limit depigmentation . Interestingly, skin resident regulatory T cells have been shown to be critical for hair follicle stem cell regeneration .…”

Programmed cell death protein 1 and vitiligo

“…Tissue‐resident memory T cell (Trm) is a recently identified T cell subset. Boniface et al found that CD8 + Trm cells were enriched in skin from patients with both active and stable vitiligo. Malik et al .…”

The convergence theory for vitiligo: A reappraisal

“…IFN‐γ responses can likewise be provoked by cutaneous commensals . Increased production of the cytokine is found among skin‐resident memory T cells reactive with melanocytes that likely contribute to disease flares and form a resource of T cells mediating antimelanoma activity . These factors highlight the importance of immune activation in vitiligo.…”