Dataset Information

PD-1 prevents pathogenicity of effector CD8 T cells that infiltrate skin under homeostatic conditions

ABSTRACT: Self-reactive T cells are part of the peripheral T cell repertoire in healthy individuals. Checkpoint receptors like PD-1 allow the establishment of peripheral tolerance by inducing deletion or anergy of self-reactive CD8 T cells, however the high frequency of immune-related Adverse Events (irAEs) among cancer patients receiving checkpoint receptor inhibitor (CPI) immunotherapy led us to question how checkpoint receptors are involved in peripheral T cell tolerance. We developed a novel mouse model for studying peripheral T cell tolerance in the skin where skin-specific expression of T cell antigens (Ags) caused local infiltration of Ag-specific CD8 T cells with effector capacity. In this setting, PD-1 was required for maintaining local tolerance by allowing the co-existence of Ag-expressing cells and Ag-specific effector CD8 T cells in skin without tissue pathology, while CD8 T cell-mediated elimination of Ag-expressing cells and consequent tissue pathology developed in the absence of PD-1-mediated regulation. In this model, PD-1 allowed maintenance of skin tolerance by preventing tissue-infiltrating Ag-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 Ag-expressing cells in the epidermis. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed 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 where PD-1 allows Ag-specific effector CD8 T cells to persist in a tissue where their cognate Ag is expressed without causing pathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229279 | GEO | 2023/05/31

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:All healthy individuals have autoreactive T cells in their peripheral T cell pool, but peripheral tolerance mechanisms prevent these T cells from causing autoimmunity. Two primary mechanisms of peripheral tolerance are T cell anergy and clonal deletion, which occur after tolerogenic priming of T cells by dendritic cells (DCs). Induction of anergy and deletion are impaired in the absence of checkpoint receptors (like PD-1), but, once established, they are not reversed by blockade of checkpoint receptors. Thus, the occurrence of immune-related Adverse Events (irAEs) in up to 70% of patients treated with checkpoint inhibitor (CPI) immunotherapy has raised questions about how checkpoint receptors are functioning to maintain peripheral tolerance of autoreactive T cells under homeostatic conditions. To address this, we developed a novel mouse model for studying peripheral T cell tolerance in the skin in which the development of localized autoimmune-like pathology was dependent on skin-infiltrating CD8 T cells following skin-specific expression of T cell antigens (Ags) and administration of PD-1 blocking antibodies. Interestingly, Ag-specific CD8 T cells were found to infiltrate Ag-expressing skin even in the absence of PD-1 blockade, however they did not cause disease and in fact co-existed with the skin cells expressing their cognate Ag. At the protein level, non-pathogenic skin-infiltrating CD8 T cells produced lower amounts of many T cell effector proteins compared to their pathogenic counterparts, explaining the lack of cutaneous pathology, but non-pathogenic T cells were functional because they remodeled the local myeloid cell compartment. Moreover, and unlike in other models of tolerance, non-pathogenic and pathogenic skin-infiltrating CD8 T cells were nearly identical at the transcriptional level, indicating that both T cell populations were differentiating towards the same effector state. In this context, checkpoint receptors prevented the majority of the non-pathogenic CD8 T cells from reaching their terminal, fully effector and pathogenic state, thus maintaining tolerance in the skin. Finally, analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed presence of clonally expanded effector CD8 T cells with comparable transcriptional profiles in both lesional and non-lesional skin. Thus, our data are in line with a model of peripheral T cell tolerance where PD-1 allows peripheral Ag-specific effector CD8 T cells to co-exist in a tissue where their cognate Ag is expressed without causing pathology and provide a mechanism for the development of cutaneous lichenoid irAEs upon administration of CPI immunotherapy.

Dataset Information

PD-1 prevents pathogenicity of effector CD8 T cells that infiltrate skin under homeostatic conditions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure