| First Author | Damo M | Year | 2023 |
| Journal | Nature | Volume | 619 |
| Issue | 7968 | Pages | 151-159 |
| PubMed ID | 37344588 | Mgi Jnum | J:341090 |
| Mgi Id | MGI:7525786 | Doi | 10.1038/s41586-023-06217-y |
| Citation | Damo M, et al. (2023) PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens. Nature 619(7968):151-159 |
| abstractText | 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(3-10). However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors(11). 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. |
