High doses of alpha-galactosylceramide potentiate experimental autoimmune encephalomyelitis by directly enhancing Th17 response.
Alpha-galactosylceramide (alpha-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 alpha-GC exacerbated, rather than ameliorated, EAE. Similar results were observed when MOG(35-55)-specific T cells treated with high-dose alpha-GC were transferred into naïve syngeneic recipient mice. Further study showed that high doses of alpha-GC directly enhance the Th17 and Th1 response by activation of CD4(+)CD44(+) memory T cells through phosphorylation of STAT3 and activation of NF-kappaB. Unlike the activation of iNKT cells by low doses of alpha-GC, high doses of alpha-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, alpha-GC treatment could improve or worsen EAE by engaging either APCs or Th17/Th1 cells depending on the dose used.
Qian
Gaochao
G
Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chong Qing Road, Shanghai 200025, China.
Qin
Xia
X
Zang
Ying Qin
YQ
Ge
Baoxue
B
Guo
Taylor B
TB
Wan
Bing
B
Fang
Lei
L
Zhang
Jingwu Z
JZ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D005699:Galactosylceramides / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D018949:Antigens, CD1; D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D005699:Galactosylceramides; D020381:Interleukin-17; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C493154:alpha-galactosylceramide