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MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and 11-23 signaling.

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Title: MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and 11-23 signaling.
Authors: JiHoon Chang1, Burkett, Patrick R.2,3, Borges, Christopher M.4, Kuchroo, Vijay K.2, Turka, Iaurence A.5 lturka@partners.org, Chang, Cheong-Hee1 heechang@umich.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 2/5/2013, Vol. 110 Issue 6, p2270-2275. 6p.
Subjects: Myeloid differentiation factor 88, T cell differentiation, T helper cells, Autoimmune diseases, Allergic encephalomyelitis, Rapamycin, Cell proliferation, Immune system
Abstract: Myeloid differentiation primary response protein 88 (MyD88) is classically known as an adaptor, linking TLR and IL-iR to downstream signaling pathways in the innate immune system. In addition to its role in innate immune cells, MyD88 has been shown to play an important role in I cells. How MyD88 regulates helper T-cell differentiation remains largely unknown, however. Here, we demonstrate that MyD88 is an important regulator of IL-17-producing CD4+ T helper cells (Th17) cell proliferation. MyD88-deficient CD4+ T cells showed a defect in Thi7 cell differentiation, but not in Thi cell or Th2 cell differentiation. The impaired IL-17 production from MyD88-deficient CD4+ T cells is not a result of defective RAR-related orphan receptor γt (RORyt) expression. In- stead, MyD88 is essential for sustaining the mammalian target of rapamycin (mIOR) activation necessary to promote Thu cell pro- liferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4+ T cells showed impaired mIOR activation and, consequently. reduced Th17 cell proliferation. Importantly, the absence of MyD88 in I cells ameliorated disease in the experimental autoimmune encephalomyelitis model. Taken together, our results demonstrate that MyD88 has a dual function in Thu cells by delivering IL-1 signaling during the early differentiation stage and integrating IL- 23 signaling to the mTOR complex to expand committed Thu cells. [ABSTRACT FROM AUTHOR]
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Abstract:Myeloid differentiation primary response protein 88 (MyD88) is classically known as an adaptor, linking TLR and IL-iR to downstream signaling pathways in the innate immune system. In addition to its role in innate immune cells, MyD88 has been shown to play an important role in I cells. How MyD88 regulates helper T-cell differentiation remains largely unknown, however. Here, we demonstrate that MyD88 is an important regulator of IL-17-producing CD4+ T helper cells (Th17) cell proliferation. MyD88-deficient CD4+ T cells showed a defect in Thi7 cell differentiation, but not in Thi cell or Th2 cell differentiation. The impaired IL-17 production from MyD88-deficient CD4+ T cells is not a result of defective RAR-related orphan receptor γt (RORyt) expression. In- stead, MyD88 is essential for sustaining the mammalian target of rapamycin (mIOR) activation necessary to promote Thu cell pro- liferation by linking IL-1 and IL-23 signaling. MyD88-deficient CD4+ T cells showed impaired mIOR activation and, consequently. reduced Th17 cell proliferation. Importantly, the absence of MyD88 in I cells ameliorated disease in the experimental autoimmune encephalomyelitis model. Taken together, our results demonstrate that MyD88 has a dual function in Thu cells by delivering IL-1 signaling during the early differentiation stage and integrating IL- 23 signaling to the mTOR complex to expand committed Thu cells. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.1206048110