PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens

Abstract

The peripheral T cell repertoire of healthy individuals contains self-reactive T cells^1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells^{3,4,5,6,7,8,9,10}. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors¹¹. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-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 epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the 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 in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.

Extrathymic peripheral T cell tolerance prevents aberrant responses by CD8 T cells that are specific for self-antigens or harmless non-self-antigens^1,2. Both T cell-intrinsic (anergy and clonal deletion) and T cell-extrinsic (T regulatory cell (T_reg)-mediated) mechanisms contribute to peripheral tolerance¹². Anergy and clonal deletion directly shape the peripheral T cell repertoire by restraining and eliminating potentially pathogenic T cells, respectively¹³. Molecular signatures of anergy and clonal deletion are characterized by a failure to acquire effector functions or infiltrate antigen-expressing tissues, and result from tolerogenic antigen presentation by dendritic cells in peripheral lymphoid organs^14,15. Peripheral tolerance breaks down in the absence of inhibition by checkpoint receptors (such as PD-1 and CTLA-4), resulting in the presence of effector CD8 T cells^3,4,5,6,7,8. However, although checkpoint receptor blockade during peripheral tolerance induction generates effector CD8 T cells, CD8 T cell anergy is not rescued by checkpoint receptor blockade once established^9,10. This suggests a binary process for peripheral tolerance induction in which checkpoint receptors determine whether tolerogenic dendritic cells drive the differentiation of the CD8 T cells towards either a tolerant or an effector state.