Characterization of CD8+ T cell Subpopulations and the Role of CD137 in Vitiligo

Vitiligo is an autoimmune disease in which CD8+ T cells selectively kill melanocytes, leading to skin depigmentation. Single-cell RNA sequencing (scRNA-seq) studies have profiled these T cells at the population level, but subpopulation characterization remains to be done. We aimed to determine the different subpopulations of CD8+ T cells in vitiligo-lesional skin and assess whether these populations differed in their clonal landscapes and spatial distributions. With this knowledge, we hoped to differentiate effector from bystander CD8+ T cells and pinpoint the effector programs driving T cell activation at sites of inflammation to develop new cell-targeted immunotherapies. To answer these questions, we combined scRNA/TCR-seq with spatial transcriptomics on vitiligo skin biopsies and performed functional experiments in vitro and in vivo. We identified four transcriptionally distinct subpopulations and focused on one population that stood out as clonally expanded and autoreactive. These CD8+ T cells infiltrate the skin throughout the body of vitiligo patients, migrate to the epidermis, and upregulate TNFRSF9 when in contact with melanocytes. During melanocyte engagement, this population coexpresses CD137/CD137L, providing a mechanism for self-stimulation. Human and mouse in vitro experiments determined that CD137 expression is required for optimal effector function, while CD137 knockout CD8+ T cells and CD137 antagonism significantly reduced disease and prevented effector retention within the skin in a mouse model of vitiligo. We also observed similar results in a mouse model of experimental autoimmune encephalomyelitis. Together, our results nominate CD137 blockade as a promising therapeutic for vitiligo and other cytotoxic T cell-driven autoimmune diseases.