Neonatally imprinted stromal cell subsets induce tolerogenic dendritic cells in mesenteric lymph nodes

Abstract

Gut-draining mesenteric lymph nodes (mLNs) are important for inducing peripheral tolerance towards food and commensal antigens by providing an optimal microenvironment for de novo generation of Foxp3+ regulatory T cells (Tregs). We previously identified microbiota-imprinted mLN stromal cells as a critical component in tolerance induction. Here we show that this imprinting process already takes place in the neonatal phase, and renders the mLN stromal cell compartment resistant to inflammatory perturbations later in life. LN transplantation and single-cell RNA-seq uncover stably imprinted expression signatures in mLN fibroblastic stromal cells. Subsetting common stromal cells across gut-draining mLNs and skin-draining LNs further refine their location-specific immunomodulatory functions, such as subset-specific expression of Aldh1a2/3. Finally, we demonstrate that mLN stromal cells shape resident dendritic cells to attain high Treg-inducing capacity in a Bmp2-dependent manner. Thus, crosstalk between mLN stromal and resident dendritic cells provides a robust regulatory mechanism for the maintenance of intestinal tolerance.

Imprinting of the immune system by the microbiota early in life

“…Stromal (fibroblastoid CD31 − gp38 + ) cells in mLN promote the generation of Tregs, a property that could be maintained in the long term upon transfer into other lymph node sites. 71 Also maintained was their distinct expression pattern, including increased expression of Retinaldehyde dehydrogenase (Raldh2/3) that converts vitamin A into RA, an efficient promoter of Tregs. 72 While imprinting of mLN could occur early in life, it was shown that imprinting could also be induced in the adult.…”

“…72 While imprinting of mLN could occur early in life, it was shown that imprinting could also be induced in the adult. 71 The nature of imprinting, probably involving epigenetic modifications, remains to be determined.…”

Seeking Windows of Opportunity to Shape Lifelong Immune Health: A Network-Based Strategy to Predict and Prioritize Markers of Early Life Immune Modulation

“…Several key immune cell populations (DCs, B cells, NK cells), reach adultlike phenotypes during the first 3 months of life, which suggests that environmental exposures during this period could have influence later in life. For example, differential susceptibility to autoimmunity and asthma may relate to DC exposure to bacterial antigens early in life, which could lead to more tolerogenic DCs later in life (27)(28)(29).…”

Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition

“…Single cell suspensions of splenocytes were prepared by meshing spleens through 30 μM cell strainers, followed by erythrocytes lysis. Single cell suspensions of lymph nodes (LNs) were prepared by enzyme-mediated digestion in RPMI 1640 medium (Gibco) containing 0.2 mg/mL DNase I (Roche), 0.2 mg/mL collagenase D (Roche) and 0.15 U/mL dispase (Roche) as described previously [ 30 ]. Colons were opened longitudinally and washed with PBS to remove feces.…”