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The balance between the responsiveness of the intestinal immune system and the gut environment is fundamental for the maintenance of intestinal homeostasis, which is required for an adequate recognition of entering antigens. The disruption of this homeostasis by exaggerated immune response to harmless antigens can lead to the development of intestinal disorders such as inflammatory bowel disease. Stromal cells are sessile non-hematopoietic cells that build the backbone of the lymph node, an important site for the immune response induction, but also contribute to immune response and tolerance induction. However, the knowledge about the role of stromal cells in the regulation of inflammatory responses is still limited. Therefore, in this study we analyzed the influence of stromal cells on the development of chronic intestinal inflammation. Here, we show that intestinal inflammation alters the immune activation of the mesenteric lymph node-derived stromal cells. Podoplanin + and CD21/35 + stromal cells showed increased expression of MHC class II molecules, but CD106 expression on CD21/35 + cells was reduced. Stromal cells secreted cytokines and chemokines such as CCL7 and CXCL16 influenced the gut-homing phenotype and proliferation of CD4 + and CD8 + T cells. Furthermore, stromal cells of peripheral lymph nodes transplanted into the mesentery attenuated colitis severity in B6- Il10 -/- mice. The reduced colitis severity in these mice was associated with increased expression of IL4 and distinct activation pattern of stromal cells derived from transplanted peripheral lymph nodes. Altogether, our results demonstrate that lymph node stromal cells impact development of chronic colitis via T cell induction. Moreover, lymph node stromal cells from different draining area due to neonatally imprinted processes distinctly regulate the induction of immune responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Basic, Peppermüller, Bolsega, Bleich, Bornemann, Bode and Buettner.)

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.

Lymph node stromal cells are known to be immunorelevant during inflammation and tolerance. Differences between peripheral lymph nodes and mesenteric lymph nodes are important for an efficient and effective immune defense. Stromal cells were considered to be perfectly adapted to their draining area and not changeable concerning their expression pattern. Here we show that stromal cells can change their profile after isolation and transplantation into a different draining area. Subsequently, these newly organized lymph nodes are able to induce not only a region-specific but also an antigen-specific immune response. Thus, stromal cells are trend-setters for immune cells in producing a microenvironment that allows an optimized immune defense.

De novo induction of Foxp3⁺ regulatory T cells (Tregs) is particularly efficient in gut-draining mesenteric and celiac lymph nodes (mLN and celLN). Here we used LN transplantations to dissect the contribution of stromal cells and environmental factors to the high Treg-inducing capacity of these LN. After transplantation into the popliteal fossa, mLN and celLN retained their high Treg-inducing capacity, whereas transplantation of skin-draining LN into the gut mesenteries did not enable efficient Treg induction. However, de novo Treg induction was abolished in the absence of dendritic cells (DC), indicating that this process depends on synergistic contributions of stromal and DC. Stromal cells themselves were influenced by environmental signals as mLN grafts taken from germ-free donors and celLN grafts taken from vitamin A-deficient donors did not show any superior Treg-inducing capacity. Collectively, our observations reveal a hitherto unrecognized role of LN stromal cells for the de novo induction of Foxp3⁺ Tregs.

Lymph nodes (LN) are highly organized and have characteristic compartments. Destruction of these compartments leads to an inability to fulfil their immunological function. However, it is not yet clearly understood which mechanisms are involved in the development and maintenance of this organization. After transplantation of LN into the mesentery, the LN regenerate to fully functional LN. In this study, the question was addressed, how stromal cells in the B-cell follicles (follicular dendritic cells), which were identified by CD21/CD35, and stromal cells in the T-cell area (gp38+ cells) are involved via chemokine signalling. The gp38+ cells and CD21/CD35+ cells were detected in the transplanted LN (EGFP, plt/plt and CXCR5(-/-) mice) over a period of 8 weeks to analyse their competence to reconstruct the compartmental organization. The presence of gp38+ cells was stable during regeneration and these cells reconstructed the T-cell area within 4 weeks. After transplantation of plt/plt LN CCL19/CCL21 expression was observed leading to partial restoration of the T-cell area. In contrast, there were changes in the presence and morphology of CD21/CD35+ cells within the B-cell area during reconstruction, which was dependent on the presence of B cells and CXCL13/CXCR5 signalling. Hence, CD21/CD35+ cells and gp38+ cells are involved in the establishment of the compartmental organization of lymph nodes but using different ways to recruit lymphocytes via chemokine signalling., (© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.)

Although the role of stromal cells has not been clearly defined, these cells have been described as forming the extracellular matrix in all lymphoid organs. Their important role in facilitating the development of immune cells in the thymus and bone marrow has long been known. In contrast, stromal cells have been found in secondary lymphoid organs and it has been shown that they are important mediators during organogenesis. More recently, their important function in the guidance and survival of immune cells has been documented. Here, we describe the important role of stromal cells within secondary lymphoid organs and highlight the fact that the immunological function of stromal cells is site-specific and unique in each lymphoid organ.