PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens

a year ago

PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens

Martina Damo, Noah I. Hornick, Aarthi Venkat, Ivana William, Kathryn Clulo, Srividhya Venkatesan, Jiaming He, Eric Fagerberg, Jennifer L. Loza, Darwin Kwok, Aya Tal, Jessica Buck, Can Cui, Jaiveer Singh, William E. Damsky, Jonathan S. Leventhal, Smita Krishnaswamy, Nikhil S. Joshi

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.

Publisher URL: https://www.nature.com/articles/s41586-023-06217-y

DOI: 10.1038/s41586-023-06217-y