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 and Nikhil S. Joshi ()
Additional contact information
Martina Damo: Yale University School of Medicine
Noah I. Hornick: Yale University School of Medicine
Aarthi Venkat: Yale University School of Medicine
Ivana William: Yale University School of Medicine
Kathryn Clulo: Yale University School of Medicine
Srividhya Venkatesan: Yale University School of Medicine
Jiaming He: Yale University School of Medicine
Eric Fagerberg: Yale University School of Medicine
Jennifer L. Loza: Yale University School of Medicine
Darwin Kwok: Yale University School of Medicine
Aya Tal: Yale University School of Medicine
Jessica Buck: Yale University School of Medicine
Can Cui: Yale University School of Medicine
Jaiveer Singh: Yale University School of Medicine
William E. Damsky: Yale University School of Medicine
Jonathan S. Leventhal: Yale University School of Medicine
Smita Krishnaswamy: Yale University School of Medicine
Nikhil S. Joshi: Yale University School of Medicine

Nature, 2023, vol. 619, issue 7968, 151-159

Abstract: Abstract The peripheral T cell repertoire of healthy individuals contains self-reactive T cells1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells3–10. 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.

Date: 2023
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DOI: 10.1038/s41586-023-06217-y

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