Molecular Mechanisms of Induction of Tolerant and Tolerogenic Intestinal Dendritic Cells in Mice

Abstract

How does the host manage to tolerate its own intestinal microbiota? A simple question leading to complicated answers. In order to maintain balanced immune responses in the intestine, the host immune system must tolerate commensal bacteria in the gut while it has to simultaneously keep the ability to fight pathogens and to clear infections. If this tender equilibrium is disturbed, severe chronic inflammatory reactions can result. Tolerogenic intestinal dendritic cells fulfil a crucial role in balancing immune responses and therefore creating homeostatic conditions and preventing from uncontrolled inflammation. Although several dendritic cell subsets have already been characterized to play a pivotal role in this process, less is known about definite molecular mechanisms of how intestinal dendritic cells are converted into tolerogenic ones. Here we review how gut commensal bacteria interact with intestinal dendritic cells and why this bacteria-host cell interaction is crucial for induction of dendritic cell tolerance in the intestine. Hereby, different commensal bacteria can have distinct effects on the phenotype of intestinal dendritic cells and these effects are mainly mediated by impacting toll-like receptor signalling in dendritic cells.

CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut

“…D). It is known that TGF‐β with TSLP helps in the maintenance of tolerance; however, under inflammatory conditions, TSLP level decreases and show increased differentiation of Th17 cells , this further supports our results on the role of TSLP promotes Tregs in culture.…”

“…The tolerogenic function of DCs and their associated molecules are well studied , and DCs mediate their regulatory function by secreting cytokines or by contact‐dependent suppression . TGF‐β and IL‐10 are the most studied molecules that are involved in Treg generation in the gut . Our results showed that Treg induction by CCR9 + DCs was not affected by IL‐10 and TGF‐β in the culture.…”

The Importance of Dendritic Cells in Maintaining Immune Tolerance

“…Finally, CD103 + CD11b + DCs also significantly contribute to immune tolerance through the expression of acyloxyacyl hydrolase, an enzyme able to inactivate LPS and thus to prevent effective TLR-4 activation that induces the differentiation of naïve T cells into effector Th17 cells (112). Altogether, these data support the view that DCs found in the gut microenvironment are geared to promote immune tolerance, likely because of the perpetual exposure to microflora and to food antigens (113). …”

Cell-intrinsic Wnt4 controls early cDC1 commitment and suppresses development of pathogen-specific Type 2 immunity

“…CD103 + CD11b -cDC are considered to be the main source of IL-12 production, although in mucosal organs they seem to have different functions in that colonic CD103 + DC suppress inflammatory responses through production of IDO1 and IL-18 binding protein; whereas CD103 + CD11b + cells are tolerogenic and promote Treg differentiation via retinoic acid 28,29 . Because intestinal cDCs can be defined by different flow cytometry gating strategies [30][31][32] , we additionally probed for cDC1 frequency using CD11b and CD172a to mark small intestine cDC2 33 . This approach revealed a selective reduction in the CD103 population within the CD11c Cre Wnt4 flox/flox mice ( Fig.…”