Thymic keratin76 shapes skin-specific central tolerance

Abstract

Keratin gene mutations are often associated with inflammatory skin disorders, in which the ensuing immunopathology is generally attributed to disrupted barrier integrity and consequent microbial invasion. Here, we challenge this paradigm by demonstrating a role for keratin 76 (Krt76) in thymic central tolerance to skin-targeting autoimmune responses. We show that transfer of Krt76-/- thymic lobes under the kidney capsules of athymic recipients is sufficient to induce expansion of effector T cells in the secondary lymphoid organs, T cell skin infiltration, and autoantibody reactivity to both skin and oral mucosa tissue. Mechanistically, we demonstrate that loss of thymic Krt76 expression disrupts canonical differentiation of the thymic medulla and impacts the development of post-AIRE-expressing keratinocyte-like mimetic medullary epithelial cells (termed CorneoTECs). Notably, Krt76-expressing CorneoTECs differentially express a specific skin and oral mucosa-associated gene signature, including skin-specific tissue self-antigens (TSAs). Importantly, in the absence of Krt76 this skin and oral mucosa TSA signature is almost entirely lost, and T cell negative selection is affected. Collectively, these data highlight a heretofore unanticipated role for Krt76 in thymic central tolerance to skin and oral mucosatargeting T cells and suggest that loss-of-keratin-associated skin disorders could also include autoimmune pathologies.

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BibTeX RIS

BibTeX

@misc{gelmetti2026thymic,
  title = {{Thymic keratin76 shapes skin-specific central tolerance}},
  author = {M. Gelmetti and I. M. Tomas and R. Ragazzini and S. Campinoti and M. S. F. Soon and M. Cautela and M. Vietri Rudan and M. Torre and N. Sumaria and I. Saldanha and D. Pereira and N. Yap and M. Efremova and Z. K. Tuong and F. M. Watt and P. Bonfanti and D. J. Pennington and I. Sequeira},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.27.747460},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.27.747460v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Thymic keratin76 shapes skin-specific central tolerance
AU  - M. Gelmetti
AU  - I. M. Tomas
AU  - R. Ragazzini
AU  - S. Campinoti
AU  - M. S. F. Soon
AU  - M. Cautela
AU  - M. Vietri Rudan
AU  - M. Torre
AU  - N. Sumaria
AU  - I. Saldanha
AU  - D. Pereira
AU  - N. Yap
AU  - M. Efremova
AU  - Z. K. Tuong
AU  - F. M. Watt
AU  - P. Bonfanti
AU  - D. J. Pennington
AU  - I. Sequeira
PY  - 2026
DA  - 2026/08/27
PB  - bioRxiv
DO  - 10.64898/2026.08.27.747460
UR  - https://www.biorxiv.org/content/10.64898/2026.08.27.747460v1
AB  - Keratin gene mutations are often associated with inflammatory skin disorders, in which the ensuing immunopathology is generally attributed to disrupted barrier integrity and consequent microbial invasion. Here, we challenge this paradigm by demonstrating a role for keratin 76 (Krt76) in thymic central tolerance to skin-targeting autoimmune responses. We show that transfer of Krt76-/- thymic lobes under the kidney capsules of athymic recipients is sufficient to induce expansion of effector T cells in the secondary lymphoid organs, T cell skin infiltration, and autoantibody reactivity to both skin and oral mucosa tissue. Mechanistically, we demonstrate that loss of thymic Krt76 expression disrupts canonical differentiation of the thymic medulla and impacts the development of post-AIRE-expressing keratinocyte-like mimetic medullary epithelial cells (termed CorneoTECs). Notably, Krt76-expressing CorneoTECs differentially express a specific skin and oral mucosa-associated gene signature, including skin-specific tissue self-antigens (TSAs). Importantly, in the absence of Krt76 this skin and oral mucosa TSA signature is almost entirely lost, and T cell negative selection is affected. Collectively, these data highlight a heretofore unanticipated role for Krt76 in thymic central tolerance to skin and oral mucosatargeting T cells and suggest that loss-of-keratin-associated skin disorders could also include autoimmune pathologies.
ER  -

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