Cbfβ2 controls differentiation of and confers homing capacity to prethymic progenitors

• Published in: The Journal of experimental medicine Vol. 215; no. 2; pp. 595 - 610
• Main Authors: Tenno, Mari, Kojo, Satoshi, Lawir, Divine-Fondzenyuy, Hess, Isabell, Shiroguchi, Katsuyuki, Ebihara, Takashi, Endo, Takaho A., Muroi, Sawako, Satoh, Rumi, Kawamoto, Hiroshi, Boehm, Thomas, Taniuchi, Ichiro
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05.02.2018; The Rockefeller University Press
• Subjects: Alternative Splicing; Animals; CBFB gene; CCR9 protein; Cell Differentiation; Cell Lineage; Core Binding Factor alpha Subunits - metabolism; Core Binding Factor beta Subunit - deficiency; Core Binding Factor beta Subunit - genetics; Core Binding Factor beta Subunit - immunology; Differentiation; Enhancer Elements, Genetic; Enhancers; Evolution, Molecular; Gene expression; Gene Knockdown Techniques; Hemopoiesis; Homing; Lymphocytes; Lymphocytes T; Lymphoid tissue; Mice; Mice, Knockout; Mice, Mutant Strains; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Phylogeny; Precursor Cells, T-Lymphoid - cytology; Precursor Cells, T-Lymphoid - immunology; Proteins; Receptors, CCR - genetics; Receptors, CCR - immunology; Ribonucleic acid; RNA; RNA, Messenger - genetics; Species Specificity; Thymus; Thymus Gland - cytology; Thymus Gland - embryology; Thymus Gland - immunology; Transcription factors; Zebrafish; Zebrafish Proteins - deficiency; Zebrafish Proteins - genetics; Zebrafish Proteins - immunology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20171221

Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbfβ forms transcription factor complexes with Runx proteins, and here we show that Cbfβ2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbfβ2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9. This occurs via direct binding of Cbfβ2 to cell type–specific enhancers, as is observed in Rorγt induction during differentiation of lymphoid tissue inducer cells by activation of an intronic enhancer. As in mice, an alternative splicing event in zebrafish generates a Cbfβ2-specific mRNA, important for ccr9 expression. Thus, despite phylogenetically and ontogenetically variable sites of origin of T cell progenitors, their robust thymus-homing capacity is ensured by an evolutionarily conserved mechanism emerging from functional diversification of Runx transcription factor complexes by acquisition of a novel splice variant.