Generation of pathogenic T_H17 cells in the absence of TGF-b signalling

Kamran Ghoreschi et al., Nature 467:967-971, 2010

Speaker: Yung-Tsai Liou (劉勇材)                                        Time: 15:00-16:00, Jun. 8, 2011

Commentator: Dr. Yee-Shin Lin (林以行 老師)                  Place: Room 601

Abstract

        The helper T cell (T_H) populations, such as T_H1, T_H2, Treg (regulatory T helper cells), and T_H17 (IL-17-secreting) cells, help eliminate pathogens.  However, recent studies showed that T_H17 cells may cause tissue damages in autoimmune diseases such as asthma, rheumatoid arthritis, and multiple sclerosis¹.  According to previous studies, in the presence of IL-1b and IL-6, TGF-b is a key initiation cytokine for T_H17 cell differentiation, and IL-23 signalling stimulates T_H17 cell expansion².  In this paper, the authors found that T_H17 cell differentiation occurred in the intestinal lamina propria of CD4dnTGF-bRII and Tgfbr1^f/fCD4-Cre⁺ mice, suggesting that T_H17 cells can be induced independent of TGF-b signalling.  Without the presence of TGF-b, increased binding of transcriptional activators histone 3 lysine 4 trimethylation (H3K4me3) and p300 to the promoters of Il17a, Il17f and Rorc, and dissociation of transcriptional repressor H3K9me3 from these promoters could be observed in the naïve CD4⁺ T cells cultured with IL-23.  Without TGF-b, the mRNA expression of Il17a and Il23r in CD4⁺ T cells could be induced by IL-23 stimulation.  The authors found that the conventional T_H17(b) cells generated by the presence of TGF-b had different gene expression profile from that of the T_H17(23) cells derived by the stimulation of IL-23.  The T_H17(23) cells highly expressed the transcriptional factor Tbx21 (homologue of human T-bet) that drives INF-g expression.  The authors demonstrated that the T_H17(23) cells expressing not only ROR-gt but also T-bet were highly pathogenic in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, in the GFP-ROR-gt reporter mice.  Adoptive transfer experiment further confirmed that the T_H17(23) cells had greater pathogenic potential than the T_H17(b) cells in Rag2^-/- mice.  In conclusion, the authors determined that the T_H17(23) cells derived by the stimulation of IL-23, but not TGF-b, represent the pathogenic T_H17 cells in autoimmunity.

References

1.      Tesmer, L.A. et al., Th17 cells in human disease. Immunol. Rev. 223:87-113, 2008

2.      Stockinger, B. & Veldhoen, M. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 19:281–286, 2007