IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

Abstract

Newly discovered IL-9–producing helper T cells (Th9) reportedly exert both aggravating and suppressive roles on experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, it is still unclear whether Th9 is a distinct Th cell subset and how IL-9 functions in the CNS. In this study, we show that IL-9 is produced by naive CD4+ T cells that were stimulated with anti-CD3 and anti-CD28 Abs under the conditions of Th2-, inducible regulatory T cell-, Th17-, and Th9-polarizing conditions and that IL-9 production is significantly suppressed in the absence of IL-4, suggesting that IL-4 is critical for the induction of IL-9 by each producing cell. The IL-9 receptor complex, IL-9R and IL-2Rγ, is constitutively expressed on astrocytes. IL-9 induces astrocytes to produce CCL-20 but not other chemokines, including CCL-2, CCL-3, and CXCL-2 by astrocytes. The conditioned medium of IL-9–stimulated astrocytes induces Th17 cell migration in vitro, which is cancelled by adding anti–CCL-20 neutralizing Abs. Treating with anti–IL-9 neutralizing Abs attenuates experimental autoimmune encephalomyelitis, decreases the number of infiltrating Th17 cells, and reduces CCL-20 expression in astrocytes. These results suggest that IL-9 is produced by several Th cell subsets in the presence of IL-4 and induces CCL-20 production by astrocytes to induce the migration of Th17 cells into the CNS.

Cytokines and effector T cell subsets causing autoimmune CNS disease

“…IL-9 induces the expression of the chemokine CCL20 by astrocytes, which enhances the migration of Th17 cells into the CNS. Accordingly mice treated with a neutralizing anti-IL-9 antibody showed reduced expression of CCL20 in astrocytes and decreased numbers of infiltrating Th17 cells resulting in reduced EAE [99].…”

Conditioned Medium from the Stem Cells of Human Exfoliated Deciduous Teeth Ameliorates Experimental Autoimmune Encephalomyelitis

“…+ T cell differentiation CD4 + CD62L + T cells were isolated from the spleen and lymph nodes of 8-wk-old female C57BL/6J mice using MACS beads (Miltenyi Biotec), as described previously (26). Cells (2 3 10 5 cells/well) were stimulated with plate-bound anti-CD3 Abs (5 mg/ml; 145-2C11) and soluble anti-CD28 Abs (2 mg/ml; 37.51; both from BD Biosciences) for 6 d in RPMI 1640 medium supplemented with 2 mM sodium pyruvate, L-glutamine, 10% FBS, and IL-2 (20 ng/ml) in the presence of 50% DMEM, 50% SHED-CM, or 100 ng/ml ED-Siglec-9/MCP-1.…”

Amazing IL-9: revealing a new function for an “old” cytokine

“…Fever that was caused by these bacterial improve antitumor immunity. IL-9 was also shown to induce CCL20 expression in astrocytes, suggesting a link between IL-9 and the infiltration of CCR6 + Th17 cells into the central nervous system during neuroinflammation (15). Interestingly, it was recently demonstrated that CCL20 could be detected in tuberculous pleural effusion as well as in supernatants of cultured pleural mesothelial cells, suggesting that human Th9 cells also express CCR6 (16).…”