IL-4/IL-13 Signaling Inhibits the Potential of Early Thymic Progenitors To Commit to the T Cell Lineage

• Published in: The Journal of immunology (1950) Vol. 199; no. 8; pp. 2767 - 2776
• Main Authors: Barik, Subhasis, Miller, Mindy M, Cattin-Roy, Alexis N, Ukah, Tobechukwu K, Chen, Weirong, Zaghouani, Habib
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 15.10.2017
• Subjects: Animals; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Differentiation; Cell Lineage; Cells, Cultured; Cytokines; Inhibition; Interleukin 13; Interleukin 4; Interleukin-13 - metabolism; Interleukin-13 Receptor alpha1 Subunit - genetics; Interleukin-13 Receptor alpha1 Subunit - metabolism; Interleukin-4 - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid cells; Myeloid Cells - physiology; Notch1 protein; Phosphorylation; Precursor Cells, T-Lymphoid - physiology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; Stat6 protein; STAT6 Transcription Factor - metabolism; T-Lymphocytes - physiology; Thymus; Thymus Gland - immunology; Transcription factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700498

Early thymic progenitors (ETPs) are endowed with diverse potencies and can give rise to myeloid and lymphoid lineage progenitors. How the thymic environment guides ETP commitment and maturation toward a specific lineage remains obscure. We have previously shown that ETPs expressing the heteroreceptor (HR) comprising IL-4Rα and IL-13Rα1 give rise to myeloid cells but not T cells. In this article, we show that signaling through the HR inhibits ETP maturation to the T cell lineage but enacts commitment toward the myeloid cells. Indeed, HR ETPs, but not HR ETPs, exhibit activated STAT6 transcription factor, which parallels with downregulation of Notch1, a critical factor for T cell development. Meanwhile, the myeloid-specific transcription factor C/EBPα, usually under the control of Notch1, is upregulated. Furthermore, in vivo inhibition of STAT6 phosphorylation restores Notch1 expression in HR ETPs, which regain T lineage potential. In addition, upon stimulation with IL-4 or IL-13, HR ETPs expressing virally transduced HR also exhibit STAT6 phosphorylation and downregulation of Notch1, leading to inhibition of lymphoid, but not myeloid, lineage potential. These observations indicate that environmental cytokines play a role in conditioning ETP lineage choice, which would impact T cell development.