Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation

• Published in: Journal of autoimmunity 2018-09, Vol.93, p.131-138
• Main Authors: Lau, Ching-In, Yánez, Diana C., Solanki, Anisha, Papaioannou, Eleftheria, Saldaña, José Ignacio, Crompton, Tessa
• Format: Article
• Language: English
• Subjects: AIRE Protein; Animals; Autoimmunity; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - immunology; Epithelial Cells - cytology; Epithelial Cells - immunology; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Foxa1; Foxa2; Gene Expression Regulation; Hepatocyte Nuclear Factor 3-alpha - deficiency; Hepatocyte Nuclear Factor 3-alpha - genetics; Hepatocyte Nuclear Factor 3-alpha - immunology; Hepatocyte Nuclear Factor 3-beta - deficiency; Hepatocyte Nuclear Factor 3-beta - genetics; Hepatocyte Nuclear Factor 3-beta - immunology; Lymphocyte Activation; Lymphocyte Count; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Organ Size; Signal Transduction; T-cell development; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; TEC; Thymocytes - cytology; Thymocytes - immunology; Thymus; Thymus Gland - cytology; Thymus Gland - immunology; Transcription Factors - genetics; Transcription Factors - immunology; Treg
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2018.07.009

The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection. Conditional deletion of Foxa1 and Foxa2 from murine TEC led to a smaller thymus with a greater proportion of TEC and a greater ratio of medullary to cortical TEC. Cell-surface MHCI expression was increased on cortical TEC in the conditional Foxa1Foxa2 knockout thymus, and MHCII expression was reduced on both cortical and medullary TEC populations. These changes in TEC differentiation and MHC expression led to a significant reduction in thymocyte numbers, reduced positive selection of CD4+CD8+ cells to the CD4 lineage, and increased CD8 cell differentiation. Conditional deletion of Foxa1 and Foxa2 from TEC also caused an increase in the medullary TEC population, and increased expression of Aire, but lower cell surface MHCII expression on Aire-expressing mTEC, and increased production of regulatory T-cells. Thus, Foxa1 and Foxa2 in TEC promote positive selection of CD4SP T-cells and modulate regulatory T-cell production and activity, of importance to autoimmunity. •Foxa1 and Foxa2 control thymic epithelial cell differentiation and T-cell selection.•Foxa1 and Foxa2 in thymic epithelial cells modulate regulatory T-cell production.•Deletion of Foxa1 and Foxa2 from TEC enhances Treg activity.