Segmented Filamentous Bacteria, DCs and Th17
It is already well described that segmented filamentous bacteria (SFB) are associated with the induction of Th17 cells in the gut, and that Th17 is associated with inflammatory bowel disease (IBD). However, the mechanisms behind the induction were not entirely clear. Yoshiyuki Goto and Casandra Panea of Columbia University Medical Center worked together to answer these questions, and found that dendritic cells (DCs) were the missing link. They determined that DCs presented SFB via MHC class II molecules to T cells, and induced SFB-directed Th17 cells. These interactions were not limited to areas of lymphoid tissue, but also happened in the small intestinal lamina propria. Interestingly, RORγt+ innate lymphoid cells simultaneously played an inhibiting role also via MHC class II molecules.
TLR6 Involved with Intestinal Inflammation
Pattern recognition receptors, like those from the Toll-like Receptor (TLR) family, alert the immune system when pathogens enter areas of the body. While this system is essential for fighting infection, the same receptors also induce inflammation during IBD. To learn more about TLR6 in intestinal inflammation, Dr. M.E. Morgan of Utrecht University in the Netherlands and her colleagues looked at immune responses induced in the gut both in vitro and in vivo. They found that stimulation of TLR6 in the gastrointestinal-associated lymphoid tissue supported the induction of Th1 and Th17 cells, and oral feeding of TLR6 ligands induced Th17 cells. Mice deficient in TLR6 had lower numbers of Th1 and Th17 cells, and were also protected from experimental colitis suggesting that TLR6 could be an interesting candidate for future IBD therapeutics.
Chromatin Control of T Cell Differentiation
Histone methyltransferases modify histones (by adding methyl groups to lysine residues) to control DNA packing and gene accessibility. These kinds changes could impact IBD. Recent research has indicated that the methyltransferase G9A controls a repressive modification called H3K9me2 that influences T cell differentiation. Dr. Frann Antignano of the University of British Columbia in Canada now sheds more light on this process. She found that G9A dynamically inhibited the differentiation of regulatory T cells and Th17, and that loss of G9A specifically led to more activity of the Foxp3 and Rorγt genes, which are the master transcription factor of regulatory T cells and Th17 cells respectively. Specifically eliminating G9A from T cells transferred during the T cell transfer colitis model increased regulatory T differentiation and lowered disease. This could mean that targeting histone methyltransferases could be a potential IBD therapy.
References
- Antignano, F., Burrows, K., & Hughes, M. R. (2014). Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation. The Journal of Clinical Investigation. doi:10.1172/JCI69592DS1
- Goto, Y., Panea, C., Nakato, G., Cebula, A., Lee, C., Diez, M. G., et al. (2014). Segmented Filamentous Bacteria Antigens Presented by Intestinal Dendritic Cells Drive Mucosal Th17 Cell Differentiation. Immunity, 1–14. doi:10.1016/j.immuni.2014.03.005
- Morgan, M. E., Koelink, P. J., Zheng, B., Brok, den, M. H. M. G. M., van de Kant, H. J., Verspaget, H. W., et al. (2014). Toll-like receptor 6 stimulation promotes T-helper 1 and 17 responses in gastrointestinal-associated lymphoid tissue and modulates murine experimental colitis. Mucosal Immunology. doi:10.1038/mi.2014.16