Glycogen synthase kinase‐3 promotes T helper type 17 differentiation by promoting interleukin‐9 production

• Published in: Immunology Vol. 160; no. 4; pp. 357 - 365
• Main Authors: Han, Dongmei, Medina‐Rodriguez, Eva M., Lowell, Jeffrey A., Beurel, Eléonore
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2020; John Wiley and Sons Inc
• Subjects: CD4 antigen; Cell differentiation; Chemokines; Cytokines; Depletion; Differentiation (biology); Gene expression; Glycogen; Glycogen synthase kinase 3; Glycogens; Helper cells; Interferon; Interferon regulatory factor; Interleukins; interleukin‐9; Kinases; Lymphocytes T; Mental disorders; Original; Receptors; Reintroduction; Retinoic acid; Stat3 protein; T helper type 17 cells; Transcription activation; Transcription factors; T helper type 17 cells; glycogen synthase kinase-3; interleukin-9
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13199

Summary T helper type 17 (Th17) cells are recognized as important contributors to the deleterious effects of several neurological and psychiatric diseases. Clarifying mechanisms that control the production of Th17 cells may therefore provide new strategies for developing novel interventions in a broad spectrum of disorders. Th17 cell differentiation is promoted by glycogen synthase kinase‐3 (GSK3), but the mechanisms for this are only beginning to be understood. Using T‐cell‐selective depletion of GSK3β and multiple selective pharmacological GSK3 inhibitors, we found that GSK3 inhibition decreased C‐C motif chemokine (ccl)20, C‐C motif chemokine receptor (ccr)6, interleukin (IL)‐9, Runt‐related transcription factor (Runx)1, interferon regulatory factor (Irf)4 and c‐maf mRNA expression after 2 days of Th17 cell differentiation in vitro. These effects were found to be independent of the master regulator transcription factor retinoic acid receptor‐related orphan receptor γT (RORγT), as GSK3 inhibition still reduced Th17 cell differentiation in RORγT‐depleted cells. Because IL‐9 was approximately ninefold down‐regulated in GSK3β−/− CD4 cells, we tested if reintroduction of IL‐9 during Th17 cell differentiation abolished the inhibition by GSK3 deficiency of Th17 cell differentiation. We found that IL‐9 over‐expression was sufficient to reverse the inhibition of Th17 cell differentiation by GSK3 inhibition or depletion. We found that IL‐9 enhances Th17 cell differentiation in part through signal transducer and activator of transcription 3 (STAT3) activation, and IL‐9 also enhances STAT3 binding to the IL‐17a promoter. Altogether, these findings suggest that IL‐9 might be an important mediator of GSK3β‐dependent enhancement of Th17 cell differentiation. Glycogen synthase kinase‐3 (GSK3) promotes Th17 cell differentiation. This study identified a network of factors regulated by GSK3 during Th17 cell differentiation. Among these, we found that GSK3 was particularly important in contributing to the promotion of Th17 cell differentiation induced by interleukin‐9.