Therapeutic implications of autoimmune vitiligo T cells

Abstract

Vitiligo is an autoimmune disease presenting with progressive loss of skin pigmentation. The disease strikes 1% of the world population, generally during teenage years. The progressive loss of melanocytes from depigmenting vitiligo skin is accompanied by cellular infiltrates containing both CD4+ and CD8+ T lymphocytes. Infiltrating cytotoxic T cells with high affinity T cell receptors have likely escaped clonal deletion in the thymus, allowing such T cells to enter the circulation. Through the expression of CLA, these T cells home to the skin where they express type 1-cytokine profiles and mediate melanocyte apoptosis via the granzyme/perforin pathway. T cells found juxtapositionally apposed to remaining melanocytes can be isolated from the skin. Vitiligo T cells have demonstrated reactivity to antigens previously recognized as target antigens for T cells infiltrating melanoma tumors. In a comparison to existing melanoma-derived T cells, vitiligo T cells displayed superior reactivity towards melanoma cells. It is thought that genes encoding the TCRs expressed by vitiligo skin infiltrating T cells can be cloned and expressed in melanoma T cells, thereby generating a pool of circulating T cells with high affinity for their targets that can re-direct the immune response towards the tumor.

Fig. 1

Lack of expression of c-KIT in lesional vitiligo skin. Sections of (A) non-lesional and (B) lesional vitiligo skin were subjected to indirect immunoperoxidase staining. Expression of the steel factor receptor was observed in non-lesional, but not in lesional skin. Original magnification 400×.

Fig. 2

Abundance of gp100 reactive T cells among lymphocytes from perilesional vitiligo skin. Lymphocytes from a progressive generalized vitiligo patient were expanded in presence of CD3/CD28 coated beads and IL-2, then reacted with fluorescently detected HLA-A2 dimers loaded with either (A) gp100 209–217 or (B) irrelevant human papillomavirus-derived immunogenic peptide, HPV16 E7 86–93, plus a fluorescent antibody to CD8, and analyzed by flow cytometry.