Stromal Cells Confer Lymph Node-Specific Properties by Shaping a Unique Microenvironment Influencing Local Immune Responses

Abstract

Lymph nodes (LN) consist not only of highly motile immune cells coming from the draining area or from the systemic circulation, but also of resident stromal cells building the backbone of the LN. These two cell types form a unique microenvironment which is important for initiating an optimal immune response. The present study asked how the unique microenvironment of the mesenteric lymph node (mLN) is influenced by highly motile cells and/or by the stromal cells. A transplantation model in rats and mice was established. After resecting the mLN, fragments of peripheral lymph node (pLN) or mLN were inserted into the mesentery. The pLN and mLN have LN-specific properties, resulting in differences of, for example, the CD103+ dendritic cell subset, the adhesion molecule mucosal addressin cell adhesion molecule 1, the chemokine receptor CCR9, the cytokine IL-4, and the enzyme retinal dehydrogenase 2. This new model clearly showed that during regeneration stromal cells survived and immune cells were replaced. Surviving high endothelial venules retained their site-specific expression (mucosal addressin cell adhesion molecule 1). In addition, the low expression of retinal dehydrogenase 2 and CCR9 persisted in the transplanted pLN, suggesting that stromal cells influence the lymph node-specific properties. To examine the functional relevance of this different expression pattern in transplanted animals, an immune response against orally applied cholera toxin was initiated. The data showed that the IgA response against cholera toxin is significantly diminished in animals transplanted with pLN. This model documents that stromal cells of the LN are active players in shaping a unique microenvironment and influencing immune responses in the drained area.

Mesenteric lymph nodes are not required for an intestinal immunoglobulin A response to oral cholera toxin

“…A strong IgA response in the intestine can be induced by oral administration of cholera toxin (CT), which is known to be one of the most potent mucosal immunogens. 9,[22][23][24] CT is also used as an adjuvant. 25 In this study, the mLNs of rats were removed and orally administered CT was used as an example of an immunogen in the gut-associated lymphoid tissue (GALT).…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…1). In LN transplantation experiments, where the hematopoietic cells of the LN were completely replaced by host cells while the stromal compartments remained donor derived, the specific T cell homing responses induced were those of the original location, rather than the transplanted location [9,69,85]. Additionally, while removal of the cervical LN blocked the induction of musosal tolerance, rescue could be achieved by transplanting a donor cervical LN but not mesenteric or peripheral LNs [86].…”

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

“…This study suggested that RA-producing stromal cells and DCs in MLN warrant the gut-tropism of activated T cells in the musoca area (131). In one elegant study of implanting MLN and peripheral LN fragments into the mesenteric region of host rat and mouse, it was established that stromal cells in MLN but not in peripheral LN provided a unique microenvironment allowing for the acquisition of a gut-tropism phenotype of T and B cells during antigen-induced activation (3,72). In addition to gut mucosa, CD103…”

“…Some studies have revealed the role of RA in maintaining the immune tolerant microenvironment in the eye through inhibition of Th1/Th17 response and promotion of Treg development. Immunization of C57BL/6 mice with human interphotoreceptor retinoid binding protein peptide 1 to 20 [IRBP (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) ] elicited experimental autoimmune uveoretinitis (EAU). Keino et al (95) reported that intraperitoneal RA administration dampened the severity of EAU when administrated at 200 g/mouse (ϳ20-fold above normal sera RA concentration, every other day) before the disease onset.…”