Damo et al. used NINJA mice to show that de novo skin-specific expression of T cell antigen in the epidermis and CPI treatment led to elimination of antigen-expressing cells and localized cutaneous disease in the mouse skin, recapitulating features of CPI-dependent lichenoid IRAEs in humans. Skin-specific antigen expression caused local infiltration of antigen-specific CD8+ T cells with an effector gene-expression profile into the dermis. PD-1 prevented epidermal infiltration of CD8+ T cells and maintained skin tolerance, which was reversed in PD-1 knockout mice. Tolerance was associated with increased interactions between antigen-specific CD8+ T cells and myeloid cells.
Contributed by Shishir Pant
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(3-10). 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.
Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. De
Author Info: (1) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (2) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. (3) Departments of Genetics and of Computer Science, Yale University School of Medicine, New Haven, CT, USA. (4) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (5) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (6) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (7) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (8) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (9) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (10) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (12) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (13) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (14) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (15) Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. (16) Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. (17) Departments of Genetics and of Computer Science, Yale University School of Medicine, New Haven, CT, USA. (18) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. nikhil.joshi@yale.edu.
