Volume 20, No 4, Apr 2010

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 20 Issue 4, April 2010: 480-491

ORIGINAL ARTICLES

High doses of α-galactosylceramide potentiate experimental autoimmune encephalomyelitis by directly enhancing Th17 response

Gaochao Qian^1,*, Xia Qin^1,*, Ying Qin Zang², Baoxue Ge³, Taylor B. Guo³, Bing Wan³, Lei Fang³ and Jingwu Z. Zhang³

¹Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chong Qing Road, Shanghai 200025, China

²Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Graduate School of CAS, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031, China

³Institute of Health Sciences, Shanghai Institute for Biological Sciences, Graduate School of CAS, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031, China Correspondence: Jingwu Z. Zhang,(jwzang@sibs.ac.cn)

α-Galactosylceramide (α-GC) is widely known to activate invariant natural killer T (iNKT) cells to suppress myelin antigen-specific Th1 responses, protecting susceptible mice against experimental autoimmune encephalomyelitis (EAE). Here, we demonstrate an unexpected finding that high doses of α-GC exacerbated, rather than ameliorated, EAE. Similar results were observed when MOG_35-55-specific T cells treated with high-dose α-GC were transferred into naïve syngeneic recipient mice. Further study showed that high doses of α-GC directly enhance the Th17 and Th1 response by activation of CD4⁺CD44⁺ memory T cells through phosphorylation of STAT3 and activation of NF-κB. Unlike the activation of iNKT cells by low doses of α-GC, high doses of α-GC directly interacted with CD1d expressed on T cells and activated Th17 and Th1 cells. Furthermore, antigen-presenting cells (APCs) predominantly express CD1d1, whereas the majority of CD4⁺ T cells express CD1d2. Knockdown of CD1d1 or CD1d2 gene expression by RNAi interfered with the activation of iNKT or Th17/Th1 cells, respectively. Therefore, α-GC treatment could improve or worsen EAE by engaging either APCs or Th17/Th1 cells depending on the dose used.

Cell Research (2010) 20:480-491. doi: 10.1038/cr.2010.6; published online 19 January 2010

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