Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease

Xuebin Liu, et al. 2010. Nat. Med. 16, 191-197

Speaker: Ting-Jing Shen (沈庭靚)                                 Time: 14:10~15:00, May, 5, 2010

Commentator: Dr. Bei-Chang Yang (楊倍昌 老師)            Place: Room 601

Abstract:

T_H17 cells play a pathogenic role in autoimmune diseases, such as multiple sclerosis characterized by chronic inflammation and demyelination of the central nervous system. To understand the differentiation and maintenance of T_H17 cells is crucial for the pathogenesis of multiple sclerosis. Recently, Il7r gene is shown to associate with multiple sclerosis¹ and elevated interleukin-7 receptor (IL-7R) and IL-7 expression were detected in the cerebrospinal fluid of multiple sclerosis patients. In this study, the authors used an experimental autoimmune encephalomyelitis (EAE) mouse model mimicking human multiple sclerosis to investigate the potential role of IL-7-IL-7R signaling in T_H17 cell development and function. They found that EAE mice treated with anti-IL-7Ra antibody showed decreases in the inflammation and demyelination of the central nervous systemaccompanied with a reduction of T_H17 cell infiltration. They demonstrated that exogenous IL-7 did not stimulate T_H17 cell differentiation in vitro. In addition, anti-IL-7Ra antibody treatment given before the onset of EAE did not affect the disease severity of mice indicating that IL-7-IL-7R signaling is not required for T_H17 cell differentiation. Instead, exogenous IL-7 treatment significantly induced the expansion of T_H17 cells from EAE mice through STAT5-dependent pathway. IL-7/STAT5 signaling pathway is important to maintain naïve CD4⁺ T cells². After the onset of EAE, T_H17 cells from EAE mice treated with anti-IL-7Ra antibody were found to undergo apoptosis with reduced anti-apoptotic protein, Bcl-2, and increased caspase-3 expression. They also found that CD4⁺CD25^- cell derived from multiple sclerosis patients treated with anti-IL-7Ra antibody reduced STAT5 phosphorylation. They further determined the selectivity of IL-7-IL-7R signaling for T_H17 cells was due to a low level of IL-7Ra expression in T_reg cells  and the expression of Socs-1, an IFN-g-inducible repressor gene, in T_H1 cells to cause the hypo-responsiveness to IL-7-IL-7R signaling. These results suggest that in EAE, IL-7-IL-7R/STAT5 is a key signaling pathway for the pathogenic T_H17 cell survival and expansion, but not differentiation, and that IL-7Ra antagonist may be a potential treatment for multiple sclerosis.

References:

1. Gregory, S.G. et al. (2007). Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. 39: 1083–1091.

2. Seki, Y. et al. (2007). IL-7/STAT5 cytokine signaling pathway is essential but insufficient for maintenance of naive CD4⁺T cell survival in peripheral lymphoid organs. J. Immunol. 178: 262–270.