PD-1 prevents pathogenicity of effector CD8 T cells that infiltrate skin under homeostatic conditions

Self-reactive T cells are part of the peripheral T cell repertoire in healthy individuals. Checkpoint receptors like PD-1 allow the establishment of peripheral tolerance by inducing deletion or anergy of self-reactive CD8 T cells, however the high frequency of immune-related Adverse Events (irAEs) among cancer patients receiving checkpoint receptor inhibitor (CPI) immunotherapy led us to question how checkpoint receptors are involved in peripheral T cell tolerance. We developed a novel mouse model for studying peripheral T cell tolerance in the skin where skin-specific expression of T cell antigens (Ags) caused local infiltration of Ag-specific CD8 T cells with effector capacity. In this setting, PD-1 was required for maintaining local tolerance by allowing the co-existence of Ag-expressing cells and Ag-specific effector CD8 T cells in skin without tissue pathology, while CD8 T cell-mediated elimination of Ag-expressing cells and consequent tissue pathology developed in the absence of PD-1-mediated regulation. In this model, PD-1 allowed maintenance of skin tolerance by preventing tissue-infiltrating Ag-specific effector CD8 T cells from 1) acquiring a fully functional, pathogenic differentiation state, 2) secreting significant amounts of effector molecules, and 3) gaining access to Ag-expressing cells in the epidermis. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance where PD-1 allows Ag-specific effector CD8 T cells to persist in a tissue where their cognate Ag is expressed without causing pathology. Skin biopsies from patients with lichenoid cutaneous immune-related adverse events (lesional skin LS1-2, nonlesional skin NLS1-2) and healthy control patients (NS1-2) were analyzed using single-cell RNA sequencing on the 10X Genomics platform.