Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development

Abdulvasey Mohammed¹, Wenqing Wang¹, Martin Arreola¹, Benjamin D Solomon², Priscila F Slepicka¹, Kelsea M Hubka¹, Hanh Dan Nguyen¹, Zihao Zheng¹, Michael G Chavez³, Christine Y Yeh^{4

5}, Doo Kyung Kim³, Michael R Ma^{6

7}, Elisabeth Martin⁷, Li Li⁸, Anca M Pasca⁸, Virginia D Winn⁹, Casey A Gifford^{10

11}, Veronika R Kedlian^{12

13}, Jong-Eun Park¹², Purvesh Khatri^{14

15}, Georg A Hollander^{16

17

18}, Maria Grazia Roncarolo¹, Vittorio Sebastiano⁹, Sarah A Teichmann^{13

19

20}, Andrew J Gentles^{4

21}, Katja G Weinacht¹

Affiliations

¹ Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94304, USA.
² Department of Pediatrics, Division of Allergy and Immunology, Stanford School of Medicine, Stanford, CA 94304, USA.
³ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
⁶ Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA.
⁷ Department of Cardiothoracic Surgery, Division of Pediatric Cardiac Surgery, Stanford University, Stanford, CA 94304, USA.
⁸ Department of Pediatrics, Division of Neonatology, Stanford School of Medicine, Stanford, CA 94304, USA.
⁹ Department of Obstetrics and Gynecology, Stanford School of Medicine, Stanford, CA, USA.
¹⁰ Department of Pediatrics, Division of Cardiology, Stanford School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Genetics, Stanford University, Stanford, CA 94305, USA.
¹² Wellcome Sanger Institute, Cambridge, UK.
¹³ Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹⁴ Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA 94304, USA.
¹⁵ Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA.
¹⁶ Department of Pediatrics and Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, UK.
¹⁷ Department of Biosystems and Engineering, ETH Zurich, Zurich, Switzerland.
¹⁸ Botnar Institute of Immune Engineering, Basel, Switzerland.
¹⁹ Department of Medicine, University of Cambridge, Cambridge, UK.
²⁰ CIFAR Macmillan Multi-scale Human Programme, CIFAR, Toronto, Canada.
²¹ Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA.

PMID: 40315299
DOI: 10.1126/sciimmunol.ado4720

Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development

Abdulvasey Mohammed et al. Sci Immunol. 2025.

. 2025 May 2;10(107):eado4720.

doi: 10.1126/sciimmunol.ado4720. Epub 2025 May 2.

Authors

Affiliations

¹ Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Stanford School of Medicine, Stanford, CA 94304, USA.
² Department of Pediatrics, Division of Allergy and Immunology, Stanford School of Medicine, Stanford, CA 94304, USA.
³ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
⁶ Cardiovascular Institute, Stanford University, Stanford, CA 94305, USA.
⁷ Department of Cardiothoracic Surgery, Division of Pediatric Cardiac Surgery, Stanford University, Stanford, CA 94304, USA.
⁸ Department of Pediatrics, Division of Neonatology, Stanford School of Medicine, Stanford, CA 94304, USA.
⁹ Department of Obstetrics and Gynecology, Stanford School of Medicine, Stanford, CA, USA.
¹⁰ Department of Pediatrics, Division of Cardiology, Stanford School of Medicine, Stanford, CA 94305, USA.
¹¹ Department of Genetics, Stanford University, Stanford, CA 94305, USA.
¹² Wellcome Sanger Institute, Cambridge, UK.
¹³ Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹⁴ Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, CA 94304, USA.
¹⁵ Center for Biomedical Informatics Research, Department of Medicine, School of Medicine, Stanford University, CA 94305, USA.
¹⁶ Department of Pediatrics and Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, UK.
¹⁷ Department of Biosystems and Engineering, ETH Zurich, Zurich, Switzerland.
¹⁸ Botnar Institute of Immune Engineering, Basel, Switzerland.
¹⁹ Department of Medicine, University of Cambridge, Cambridge, UK.
²⁰ CIFAR Macmillan Multi-scale Human Programme, CIFAR, Toronto, Canada.
²¹ Department of Pathology, Stanford School of Medicine, Stanford, CA 94305, USA.

PMID: 40315299
DOI: 10.1126/sciimmunol.ado4720

Abstract

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.

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Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development

Affiliations

Distinct type I and II interferon responses direct cortical and medullary thymic epithelial cell development

Authors

Affiliations

Abstract

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