Inflammatory Th1 and Th17 in the Intestine Are Each Driven by Functionally Specialized Dendritic Cells with Distinct Requirements for MyD88

Abstract

Summary Normal dynamics between microbiota and dendritic cells (DCs) support modest numbers of T cells, yet these do not cause inflammation. The DCs that induce inflammatory T cells and the signals that drive this process remains unclear. Here we demonstrate that small intestine DCs lacking the signaling attenuator A20 induce inflammatory T cells and that the signals perceived and antigen presenting cell (APC) functions are unique for different DC subsets. Thus, while CD103+CD11b− DCs exclusively instruct IFNγ+ T cells, CD103+CD11b+ DCs exclusively instruct IL-17+ T cells. Surprisingly, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103−CD11b+ DCs instruct both IFNγ+ and IL-17+ T cells and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis both CD103− CD11b+ and CD103+CD11b+ DCs expand pathologic Th17 cells. Thus, in disease pathogenesis specific DCs instruct specific inflammatory T cells.

Indole-3-Pyruvic Acid, an Aryl Hydrocarbon Receptor Activator, Suppresses Experimental Colitis in Mice

“…CD103 + CD11b 2 DCs are unique cells that can cross-present Ag to CD8 + T cells (50). CD103 2 CD11b + DCs induce the differentiation of both IFN-g and IL-17-producing effector T cells (36,51,52). CD103 2 DCs, mainly composed of CD103 2 CD11b + DCs, are highly inflammatory during chronic colitis (53,54).…”

The Th17/Treg Cell Balance: A Gut Microbiota-Modulated Story

“…Blockade of the P2X7 receptor abrogated the levels of these cytokines [113]. As ATP is presumed to be an important factor in the pathogenesis of inflammatory bowel disease [114,115], Atarashi et al administered ATP to mice and found that it exacerbated T-cell-mediated enterocolitis [116]. While P2X and P2Y receptors are expressed on many cells including myeloid and lymphoid cells [117], Liu et al have shown, using a microbiota antigen-specific T cell reporter mouse system, that TLR5 mediates the induction of intestinal Th17 cells by CD172α + lamina propria dendritic cells [115].…”

Irgm1-deficiency leads to myeloid dysfunction in colon lamina propria and susceptibility to the intestinal pathogenCitrobacter rodentium

“…There are three DC subsets in colon and all three were significantly reduced in C. rodentium infected Irgm1 -/mice (Fig 5f-h). The subsets most significantly affected were CD103 + CD11band CD103 -CD11b + DCs, both of which instruct intestinal Th1 responses [38][39][40][41]. CD103 -CD11b + DCs were unique in that their abundance was profoundly reduced in both infected and uninfected Irgm1 -/mice (Fig, 6f).…”

“…Colon lamina propria were processed as described [39] Briefly, colon was cut longitudinally and washed thoroughly to remove luminal contents. Colon was then cut into 0.3cm pieces and washed twice for 10 minutes in HBSS/10mM HEPES/0.035% NaHCO3/5mM EDTA/1.25% BSA/1mM DTT, followed by another 10 min wash in HBSS/10mM HEPES/0.035% NaHCO3/1.25%BSA.…”