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Liver Kinase B1 isoform expression as a regulator of T cell phenotypic stability

Abstract
Following activation, CD4 T cells undergo extensive metabolic and transcriptional changes to respond to external cues and differentiate into T helper (Th) cell subsets. This differentiation process was originally perceived to be terminal. However, it has been shown that T cells exhibit plasticity between subsets in the context of highly inflammatory environments. This phenomenon is especially prevalent in autoimmune conditions such as colitis and multiple sclerosis in which high levels of IL-6 promote considerable plasticity between regulatory T (Treg) cells and Th17 cells. Herein we show that Liver Kinase B1 (LKB1), a metabolic sensor that enforces energy-preserving mechanisms such as fatty acid oxidation (FAO), is spliced into its short isoform in Th17 cells but not in induced (i)Tregs. We demonstrate that, in Th17 cells, heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) binds to transcripts of Stk11, which encodes LKB1, and this correlates with alternative splicing into its short splice variant (Stk11S).When we neutralize hnRNPLL function using a cell-penetrating antibody, we observe diminished Stk11S expression. We further show that hnRNPLL and Stk11S, both, are regulated by the T cell-specific kinase, Protein Kinase C theta (PKCq) in Th17 cells. We provide additional evidence that, in iTregs exposed to IL-6, Prkcq, Stk11S, and Rorc are all upregulated, suggesting iTreg-Th17 plasticity is induced in response to IL-6 and culminates in Stk11 splicing downstream of PKCq. Finally, we demonstrate a link between Stk11 splicing and Th17 metabolism, showing that functionally inhibiting hnRNPLL modulates expression of the key glycolytic enzyme, Hexokinase 2, and inhibiting glycolysis, in turn, modulates the expression of Stk11S. Our data reveal an as-yet- undescribed outside-in signaling pathway downstream of IL-6 that acts through PKCq and hnRNPLL to regulate splice variants of Stk11 in Th17 cells. Furthermore, we show for the first time that this pathway can also be initiated in iTregs exposed to IL-6, providing mechanistic insight into iTreg-Th17 plasticity.
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openaccess
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dissertation
Date
2020-12-18
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