Normal proportion and expression of maturation markers in migratory dendritic cells in the absence of germs or Toll‐like receptor signaling

Abstract

Dendritic cells (DCs) play major roles in immunosurveillance. In peripheral tissues, 'immature' DCs are dedicated to capturing antigens. Detection of pathogens through Toll-like receptors (TLRs) triggers DC migration to the lymph nodes (LNs), where they acquire a 'mature' phenotype specialized at presenting antigens. However, DCs migrate from tissues and mature even in the absence of overt infections. This has been attributed to detection of commensal flora in the skin, the gut or other peripheral tissues in the steady state. To test this assumption, we have analyzed the DCs contained in the lymphoid organs of germ-free mice and of mice lacking the TLR adapter molecules, MyD88 and TRIF. We show that the proportion and expression of maturation markers in DC immigrants in the LNs of these mice are similar to those in normal mice. These results suggest that DC migration from tissues, followed by their phenotypic maturation, is regulated in the steady state by an inherent program of DC differentiation or by the release of low levels of inflammatory signals from normal tissues.

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

“…Although compounds derived from the microbiota influence immune homeostasis in both MyD88-dependent and -independent manners (41, 42), we show in this work that mesenteric lymph from germ-free mice contains a normal proportion of DCs, and that treatment of conventionally housed WT mice with broad-spectrum antibiotics has no effect on the accumulation rate of intestinal CD103 + DCs in the MLN. These results are in agreement with previous observations of similar phenotype and function of DCs in MLN of germ-free and conventionally housed rodents (31,43,44), and collectively argue against a direct role for the gut microbiota in driving the MyD88-dependent steady-state migration of SI LP CD103 + DCs. It still, however, remains possible that TLR ligands present in the food and/or produced by enteric viruses could account for the MyD88 dependency in this process.…”

“…Although the proportion of CD205 + CD8a 2 cells among total MLN DCs has been shown to be comparable between MyD88 2/2 and WT mice (31), flow cytometry analysis of MHC-II high DCs revealed that the CD205 + CD8a 2 phenotype does not fully encompass all migratory DCs in the MLN (Supplemental Fig. 1).…”

From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets

“…pDC, similar to committed precursors of classical DC, enter lymphoid organs directly from the blood through the high endothelial venules [13][14][15]. Under homeostatic conditions, pDC also inhabit mucosal tissues and organs, albeit at low numbers.…”

“…Consistent with a role in the maintenance of tolerance to skin-derived self-proteins, each of the five identified skin DC subsets migrate to CLN in the absence of inflammation [10,15]. In steady-state CLN, skinderived DC express levels of MHC class II (MHCII) molecules and of costimulatory molecules (CD86 and CD40) that are as high as those found on skinderived DC that reach CLN under inflammation [4,16].…”

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

“…29 Importantly, both of the lymph node immigrant subsets are activated upon entering the lymph node, most likely in response to stimuli encounter in the peripheral tissue. 30 This enables examination of autophagy components in cross-presenting (CD103 C ) and noncross-presenting (CD103 ¡ ) DC activated without external intervention. CD103 C DC freshly isolated from skin-draining lymph nodes displayed many more SQSTM1 aggregates per cell than CD103 ¡ DC or CD8 C DC isolated from the same lymph nodes (Fig.…”