Barik Subhasis, Miller Mindy M, Cattin-Roy Alexis N, Ukah Tobechukwu K, Chen Weirong, Zaghouani Habib
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212.
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212;
J Immunol. 2017 Oct 15;199(8):2767-2776. doi: 10.4049/jimmunol.1700498. Epub 2017 Sep 11.
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.
早期胸腺祖细胞（ETP）具有多种潜能，能够产生髓系和淋巴系祖细胞。胸腺环境如何引导ETP定向分化并成熟为特定谱系仍不清楚。我们之前已经表明，表达由IL-4Rα和IL-13Rα1组成的异源受体（HR）的ETP会产生髓系细胞而非T细胞。在本文中，我们表明通过HR发出的信号会抑制ETP向T细胞谱系的成熟，但会促使其向髓系细胞定向分化。事实上，HR ETP（而非其他ETP）表现出活化的STAT6转录因子，这与T细胞发育的关键因子Notch1的下调同时出现。与此同时，通常受Notch1调控的髓系特异性转录因子C/EBPα上调。此外，体内抑制STAT6磷酸化可恢复HR ETP中Notch1的表达，使其重新获得T谱系潜能。另外，在用IL-4或IL-13刺激后，表达病毒转导HR的HR ETP也表现出STAT6磷酸化和Notch1的下调，导致淋巴系而非髓系谱系潜能受到抑制。这些观察结果表明，环境细胞因子在调节ETP谱系选择中发挥作用，这将影响T细胞发育。
