LRRK2 G2019S mutation suppresses differentiation of Th9 and Treg cells via JAK/STAT3

Output Details

The Leucine-rich repeat kinase-2 (LRRK2) G2019S mutation, resulting in aberrantly enhanced kinase activity, is one of the well-recognized genetic risk factors in Parkinson's Disease (PD). Increased LRRK2 activity was also observed in immune cells from PD patients. Emerging results have also unveiled an upsurge in alpha-synuclein (alpha-syn)-specific CD4+ T cell responses in PD patients. Given that LRRK2 mutations in PD are germline mutations, there are unmet meets to explore whether LRRK2 G2019S mutation contributes to the pathogenesis of PD via altering CD4+ T-cell functions. To fill this knowledge gap, we generated a new T cell receptor (TCR) transgenic mouse strain bearing LRRK2 G2019S knock-in mutation, OT-II/LRRK2 (Refer to Mut). As CD4+ T cells from OT-II mice specifically recognize ovalbumin, this new strain enables us to explore the impact of LRRK2 G2019S mutation on T-cell functions in an antigen-specific manner. We found that the abundance and proliferation of major immune subsets in spleen tissue from Mut mice are comparable to wild-type (OT-II, Refer to WT) control. However, when we characterized T cell differentiation in these two strains, T cells derived from Mut mice displayed increased Th2 differentiation (IL-4) and decreased Th9 (IL-9) and Treg (Foxp3+ %) differentiation. LRRK2 G2019S mutation significantly altered the expression levels of master transcription factors (TFs) for T cell differentiation. Specifically, Mut T cells displayed an increase in mRNA expression of Gata3 (TF for Th2), a decrease in expression of Irf4 and Foxp3 (TFs for Th9 and Treg, respectively). Mechanistically, LRRK2 mutation decreased IL-9 production and Treg cell population through the JAK/STAT3 signaling. In conclusion, LRRK2 plays a critical role in regulating T cell differentiation, warranting further studies to evaluate the impacts of altered T cell differentiation led by LRRK2 mutation in dopaminergic neuron damages.
Tags
  • Adaptive immune cells
  • Differentiation
  • Immune response
  • LRRK2
  • Neuro-immune interaction
  • T cells

Meet the Authors

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    Ningbo Zheng, PhD

    Key Personnel: Team Chen

    University of Houston

  • Roshni Jaffery, BSc

    Key Personnel: Team Chen

    University of Houston

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    Ashley Guerrero

  • Jiakai Hou, PhD

    Key Personnel: Team Chen

    University of Houston

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    Yuchen Pan

  • User avatar fallback logo

    Fang Zhou, PhD

    Key Personnel: Team Chen

    Massachusetts General Hospital

  • User avatar fallback logo

    Si Chen

  • User avatar fallback logo

    Chunyu Xu, PhD

    Key Personnel: Team Chen

    University of Houston

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    Nicholas A. Egan

  • User avatar fallback logo

    Ritu Bohat

  • User avatar fallback logo

    Ken Chen

  • Michael Schwarzschild, MD

    Co-PI (Core Leadership): Team Chen

    Harvard University

  • Xiqun Chen

    Lead PI (Core Leadership): Team Chen

    Massachusetts General Hospital

  • Weiyi Peng, PhD

    Co-PI (Core Leadership): Team Chen

    University of Houston