Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development
Advances in genomics have redefined our understanding of thymic epithelial heterogeneity and architecture, yet signals driving thymic epithelial differentiation remain incompletely understood. Here, we elucidated pathways instructing human thymic epithelial cell development in the context of other anterior foregut-derived organs. Activation of interferon response gene regulatory networks distinguished epithelial cells of the thymus from those of other anterior foregut-derived organs. Thymic cortex and medulla epithelia displayed distinctive interferon-responsive signatures defined by lineage-specific chromatin accessibility. We explored the effects of type I and II interferons on thymic epithelial progenitor differentiation from induced pluripotent stem cells. Type II interferon was essential for expressing proteasome and antigen-presenting molecules, whereas type I or II interferons were essential for inducing different cytokines in thymic epithelial progenitor cells. Our findings suggest that interferons are critical to cortical and medullary thymic epithelial cell differentiation.
Authors
- Doo Kyung Kim (ORCID: https://orcid.org/0000-0002-1181-3336)
- Maria Grazia Roncarolo (ORCID: https://orcid.org/0000-0003-1636-1495)
- Li Li (ORCID: https://orcid.org/0000-0001-7886-6056)
- Vittorio Sebastiano (ORCID: https://orcid.org/0000-0002-8498-8655)
- Christine Y. Yeh (ORCID: https://orcid.org/0000-0003-4217-8555)
- Andrew J. Gentles (ORCID: https://orcid.org/0000-0002-0941-9858)
- Michael Ma (ORCID: https://orcid.org/0000-0002-1367-2071)
- Sarah Amalia Teichmann (ORCID: https://orcid.org/0000-0002-6294-6366)
- Benjamin D. Solomon (ORCID: https://orcid.org/0000-0003-1009-7312)
- Veronika R. Kedlian (ORCID: https://orcid.org/0000-0001-6563-0829)
- Casey A. Gifford (ORCID: https://orcid.org/0000-0002-7757-573X)
- Priscila Ferreira Slepicka (ORCID: https://orcid.org/0000-0002-1006-6965)
- Virginia D. Winn (ORCID: https://orcid.org/0000-0003-1136-2907)
- Kelsea M. Hubka (ORCID: https://orcid.org/0000-0002-9641-8908)
- Anca M. Pașca (ORCID: https://orcid.org/0000-0002-0445-9009)
- Abdulvasey Mohammed (ORCID: https://orcid.org/0009-0009-1717-5572)
- Élisabeth Martin (ORCID: https://orcid.org/0000-0002-6259-7813)
- Katja G. Weinacht (ORCID: https://orcid.org/0000-0002-4907-8293)
- Zihao Zheng (ORCID: https://orcid.org/0009-0008-9113-6646)
- Purvesh Khatri (ORCID: https://orcid.org/0000-0002-4143-4708)
- Georg A. Holländer (ORCID: https://orcid.org/0000-0002-8790-0874)
- Hanh Dan Nguyen
- Jong-Eun Park (ORCID: https://orcid.org/0000-0002-1687-2423)
- Martin Arreola (ORCID: https://orcid.org/0009-0001-3703-4760)
- Wenqing Wang
- Michael G. Chavez (ORCID: https://orcid.org/0000-0002-4699-8246)
Institutions
- Canadian Institute for Advanced Research (CA)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Cardiovascular Institute of the South (US)
- Wellcome Sanger Institute (GB)
- ETH Zurich (CH)
- Regenerative Medicine Institute (MX)
- Stanford Medicine (US)
- Institute of Infection and Immunity (CA)
- Stanford University (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1126/sciimmunol.ado4720
- Citations
- 4
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 3.19