BACE1 is a novel regulator of Th17 function in EAE

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Gerard Hernandez Mir
thesis / dissertation description
Th17 cells are implicated in autoimmune disease, including attack of the central nervous system (CNS) in multiple sclerosis. β-site APP-cleaving enzyme 1 (BACE1) is a membrane protease expressed in neurons and astrocytes. BACE1 is best known for its role in promoting neurodegeneration in Alzheimer’s disease by cleaving amyloid precursor protein, although it also plays a critical role in driving myelination of the central and peripheral nervous system. In addition, BACE1 has been reported to contribute to lesion severity following brain injury, as has IL-17A, although these two molecules have not previously been linked. Here, we show that in vitro-differentiated BACE1-/- Th17 cells exhibited reduced IL-17A and CD73 production despite regular RORγt upregulation. Expression of IL-17F was mildly reduced while other prototypic Th17 molecules remained unaltered, such as RORγt, IL-23R or GM-CSF. BACE1 regulation of IL-17A and CD73 occurred in a T cell intrinsic manner and its deficiency impaired the pathogenic function of Th17 cells in different models of EAE. Although affected by BACE1 deficiency, CD73-deficient animals did not exhibit decreased IL-17 production or reduced encephalitogenicity. Mechanistically, BACE1-deficiency resulted in reduced expression of PTEN and increased production of cAMP by the adenylate cyclase (AC). Concomitantly with imbalanced PTEN, BACE1-/- T cells exhibited higher phosphorylation of Akt upon T cell activation. Accordingly, forskolin-induced activation of the AC as well as PTEN hemideletion or pharmacological blockade phenocopied the findings observed in BACE1-/- Th17 cells. In summary, our data demonstrate that BACE1 is a novel regulator of Th17 function but does not impact Th17 differentiation. By modulating cAMP and PTEN levels, BACE1 can couple early signaling events, such as T cell activation and Ca2+ signaling, with the specific regulation of IL-17A and CD73 expression in Th17 cells. These findings highlight BACE1 as a novel potential therapeutic target to treat IL-17A-driven autoimmune disorders.