Role of Blimp-1 in programing Th effector cells into IL-10 producers
| Autor: | Alexander Scheffold, Markus M. Heimesaat, Anja A. Kühl, Marko Janke, Katrin Neumann, Frederik Heinrich, Christine Rudolph, Christian Neumann, Jonas Ahlers, Victoria Junghans, Andreas Radbruch, Mir-Farzin Mashreghi, Nadine Mockel-Tenbrinck, Sin-Hyeog Im, Sascha Rutz, Charlotte Esser |
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| Rok vydání: | 2014 |
| Předmět: |
Immunology
Mice Transgenic Article Mice Interleukin 21 Transforming Growth Factor beta Animals Immunology and Allergy IL-2 receptor Interleukin 27 Interleukin 3 Mice Knockout CD40 Receptors Notch biology Interleukins Transforming growth factor beta STAT4 Transcription Factor Th1 Cells Interleukin-12 Interleukin-10 3. Good health Mice Inbred C57BL Interleukin 10 Proto-Oncogene Proteins c-maf biology.protein Interleukin 12 Cancer research Positive Regulatory Domain I-Binding Factor 1 Toxoplasmosis Signal Transduction Transcription Factors |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20131548 |
| Popis: | The transcriptional regulator Blimp-1 is absolutely required for IL-10 production in Th1 cells and limits inflammatory effector T cell responses downstream of IL-12 and IL-27. Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1–dependent to a Blimp-1–independent pathway in IL-27–induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine. |
| Databáze: | OpenAIRE |
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