TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells

Increasing evidence suggests that TLRs are involved in the pathogenesis of liver diseases; however, the underlying mechanisms remain obscure. In this study, we found that treatment with CpG-oligodeoxynucleotide (ODN) promoted the accumulation and activation of murine hepatic NKT cells. Additional experiments showed that CpG-ODN preferred to act on CD4(+) NKT cells, while having less effect on CD4(-) NKT cells. The effect of CpG-ODN on liver NKT cells depended on the presence of Kupffer cells and IL-12. Meanwhile, CpG-ODN pretreatment aggravated liver injury and promoted the production of inflammatory cytokines in a Con A-induced fulminant hepatitis model via TLR9 activation. Collectively, our data demonstrate that TLR9 stimulation prefers to promote the accumulation and activation of hepatic CD4(+) NKT cells and suggest that TLR9 signaling might be involved in the pathogenesis of human hepatitis. The Journal of Immunology, 2009, 182: 3768-3774.