Commensal DNA Limits Regulatory T Cell Conversion and Is a Natural Adjuvant of Intestinal Immune Responses

Jason A. Hall et al. 2008. Immunity 29: 637-649.

Speaker: Yu-Lun Cheng (鄭宇倫)                                                   Time: 13:10~14:00, Feb. 25, 2009

Commentator: Chun-Keung Yu, Ph. D. (余俊強老師)                    Place: Room 601

Abstract:

Gut-associated lymphoid tissues (GALTs) are immune system in the digestive tract. There are many immune cells in different anatomical positions, such as Peyer’s patch (PP), intestinal lamina propria (LP), mesenteric lymph node (MLN). In the digestive tract, not only immune cells but also intestinal epithelial cells highly express toll-like receptors (TLRs) (1). Recognition of commensal flora by TLRs is required for intestinal homeostasis (2) but the mechanism is not completely clear. Previous study demonstrated that regulatory T cells (Treg cells) involved in protection in GALTs (3). And two sites of Tlr9 sequence are associated with inflammatory bowel diseases (4). So authors presumed that gut-flora DNA and TLR9 influence Treg cells and subsequently local immune responses in the gut. In this article, the data show that population of CD4⁺Foxp3⁺ cells increased in small intestine from Tlr9^-/- mice compared from wild type mice (WT mice). And then, cytokine production, such as IFN-γ and IL-17, decreased in small intestine from Tlr9^-/- mice. Next, authors analyzed immune response about TLR9 to oral infection and vaccination. In Tlr9^-/-mice, IFN-γ and IL-17 production induced by oral infection with Encephalitozoon cuniculi spores were impaired. Using bone-marrow chimeric mice, authors found out that TLR9 engagement by hematopoietic-derived cells is sufficient for modulation of Treg cell frequencies and priming the gut for immune responsiveness. Screened the TLR2, TLR4, TLR5, and TLR9 signaling, naïve T cells did not convert to Treg cells through TLR9 signaling. And TLR9 signaling enhanced cytokine production in local effector T cells (Teff cells). Finally, TLR9 ligands, both CpG DNA and gut-flora DNA (gfDNA), can inhibit T cell conversion by lamina propria dendritic cells in a TLR9-dependant manner. However, gfDNA elevated intestinal immune responses, including IFN-γ and IL-17 production and defense against oral infection. So gfDNA served as a natural adjuvant to regulate Treg cell frequencies and Teff cell activities.

References:

1.    Takeda, K. et al. 2003. Toll-like receptors. Annu. Rev. Immunol. 21: 335-376.

2.    Rakoff-Nahoum, D. et al. 2004. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118: 229-241.

3.    Izcue, A. et al. 2006. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212: 256-271.

4.    Torok, H. P. et al. 2004. Crohn’s disease is associated with a toll-like receptor-9 polymorphism. Gastroenterology 127: 365-366.