LRRK2G2019S mutation suppresses differentiation of Th9 and Treg cells via JAK/STAT3

Abstract

AbstractThe 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 α-synuclein (α-syn)-specific CD4+T cell responses in PD patients. Given thatLRRK2mutations in PD are germline mutations, there are unmet meets to explore whetherLRRK2G2019S 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 bearingLRRK2G2019S 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 ofLRRK2G2019S 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.LRRK2G2019S 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 ofGata3(TF for Th2), a decrease in expression ofIrf4andFoxp3(TFs for Th9 and Treg, respectively). Mechanistically,LRRK2mutation 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 byLRRK2mutation in dopaminergic neuron damages.