Loss of Keratin 76 in Thymic Epithelial Cells affects Skin Tissue Self-Antigens presentation in the Thymus and disrupts T cell tolerance

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"Keratins are cytoskeletal proteins expressed in epithelial cells, including medullary thymic epithelial cells (mTECs). Recent studies have uncovered a role for keratins in regulating immunity (Hobbs et al., 2015). Keratin76 (Krt76) is expressed in epithelial cells of the oral cavity, squamous stomach and thymus, and was shown to play an immunomodulatory role in oral and gastric cancer (Sequeira et al., 2018). Krt76-/- adult mice display a chronic inflammation phenotype, however, it remains unclear how thymic epithelial cells (TECs) expressing Krt76 are interacting with and regulating the immune system.I aim to investigate how loss of Krt76 specifically in the thymus impacts T cell development and demonstrate its role in communicating with cellular components to regulate the expression of skin-specific tissue self-antigens (TSAs) within the thymus. We identified co-expression of Krt76 amongst other terminally differentiated mTEC markers and in human and mice Hassall's Corpuscles, unique thymic structures with an unclear function. We transplanted foetal Krt76-/- thymi into the renal capsule of athymic nude mice which confirmed that adult Krt76-/- inflammatory phenotype was driven by Krt76 disruption specifically in the thymus. We hypothesised that Krt76+ TECs may be responsible for the expression of TSAs, based on the recent study by Michelson et al. (Cell 2022). Analysis of their published dataset indicated expression of specific skin TSAs by Krt76+ mTECs. Additionally, we carried out scRNA-seq of Krt76-/- thymi to investigate the cellular and molecular differences in the Krt76-/- thymi, and assessed the molecular mechanisms regulating these changes. Additionally, flow cytometry and immunohistochemistry analysis revealed higher numbers of effector T cells in the periphery of young adult Krt76-/- mice, but not at earlier timepoints. Our results confirm that keratins in the thymus can impact the maturation of T cells, in particular by priming T cells specifically against skin TSAs. This study highlights the fundamental role of keratins in tightly regulated immunological processes. This study places Krt76+ TECs in direct communication with skin immune homeostasis, which could present as a major new target for future therapeutic interventions."