Role of different dendritic cell subsets in vivo

To understand the roles of various gut dendritic cell (DCs) subsets in controlling intestinal inflammation, two DTR mice strains: Clec9A DTR and Clec4a4 DTR, capable of conditional in vivo ablation of respective colonic CD103+ CD11b- and CD103+ CD11b+ DCs have been generated. In a dextran sodium sulphate (DSS) model of colonic inflammation, ablation of CD103+ CD11b- colonic DCs resulted in exacerbated colitis, while ablation of colonic CD103+ CD11b+ DCs resulted in resistance to colitis when subjected to the same DSS regiment. Hence our results highlight the opposing roles of these two distinct colonic DC subsets in controlling DSS-induced colonic inflammation. A cross-talk between DCs, other gut immune cells and the colonic epithelia, involved in maintenance of a functional mucosal epithelial barrier, has been proposed to directly impact outcome of colonic inflammation. The mechanistic details of how these distinct DC subsets contribute to regulate colonic inflammation will be discussed.DOCTOR OF PHILOSOPHY (SBS

Long-lived innate IL-17–producing γ/δ T cells modulate antimicrobial epithelial host defense in the colon

Intestinal IL-17–producing cells, including Th17, γ/δ T, and innate lymphoid cells, are differentially distributed along the gastrointestinal tract. In this study, we show that the gut IL-17–producing γ/δ T (γ/δ T17) cells develop before birth and persist in the tissue as long-lived cells with minimal turnover. Most colon γ/δ T17 cells express, together with Vγ4 and CCR6, the scavenger receptor 2 and are mainly restricted to innate lymphoid follicles in the colon. Colon γ/δ T cells in mice that lack conventional dendritic cells 2 produced increased amounts of IL-17 with concomitant heightened epithelial antimicrobial response, such as the C-type lectins Reg3γ and Reg3β. In the absence of γ/δ T cells or after IL-17 neutralization, this epithelial response was dramatically reduced, underlining the protective role of this unique subpopulation of innate γ/δ T17 cells in the colonic mucosa.MOE (Min. of Education, S’pore

Intestinal CD103+CD11b− dendritic cells restrain colitis via IFN-γ-induced anti-inflammatory response in epithelial cells

A crosstalk between commensals, gut immune cells, and colonic epithelia is required for a proper function of intestinal mucosal barrier. Here we investigated the importance of two distinct intestinal dendritic cell (DC) subsets in controlling intestinal inflammation. We show that Clec9A–diphtheria toxin receptor (DTR) mice after depletion of CD103+CD11b− DCs developed severe, low-dose dextran sodium sulfate (DSS)-induced colitis, whereas the lack of CD103+CD11b+ DCs in Clec4a4-DTR mice did not exacerbate intestinal inflammation. The CD103+CD11b− DC subset has gained a functional specialization that able them to repress inflammation via several epithelial interferon-γ (IFN-γ)-induced proteins. Among others, we identified that epithelial IDO1 and interleukin-18-binding protein (IL-18bp) were strongly modulated by CD103+CD11b− DCs. Through its preferential property to express IL-12 and IL-15, this particular DC subset can induce lymphocytes in colonic lamina propria and in epithelia to secrete IFN-γ that then can trigger a reversible early anti-inflammatory response in intestinal epithelial cells.MOE (Min. of Education, S’pore)NMRC (Natl Medical Research Council, S’pore)Published versio