Antigen‐dependent rescue of nose‐associated lymphoid tissue (NALT) development independent of LTβR and CXCR5 signaling

Abstract

Nose-associated lymphoid tissue (NALT) in the rodent upper respiratory tract develops postnatally and is considered to be independent of several factors known to be involved in the organogenesis of LN and Peyer's patches (PP). In this study we demonstrate that at least two different pathways result in NALT development. Following NALT anlage formation the intrinsic pathway relies on a signaling cascade including those mediated through the chemokine receptor CXCR5 and the lymphotoxin b receptor (LTbR). This allows for the formation of high endothelial venules and thereby the recruitment of lymphocytes into NALT. Alternatively, high endothelial venule formation and lymphocyte recruitment can be induced in the NALT anlage by environmental signals, which are independent of LT-bR and chemokine receptor CXCR5 signaling but in part rely on CD40 ligand. Thus, our study identifies a novel mechanism that facilitates the rescue of NALT development at late stages in adult life independent of the canonical LTbR-CXCR5 signaling axis.Key words: Chemokines . Developmental immunology . Lymphoid organs Supporting Information available online IntroductionMucosal surfaces are equipped with dedicated mucosa-associated lymphoid tissues that facilitate the induction of mucosal immune responses. Nose-associated lymphoid tissue (NALT) in the rodent upper respiratory tract belongs to these specialized structures [1]. Due to its close proximity to entry sites of foreign and infectious agents NALT is an important inductive tissue for the generation of long lasting mucosal immunity in the upper respiratory tract and in the oral cavity [2][3][4][5][6]. NALT represents a paired lymphoid structure localized cranially to the soft palate at the bifurcated pharyngeal duct of rodents. Each part of the organ is composed of follicle-associated epithelium, high endothelial venules (HEV), T-and B-cell-enriched areas as well as DC [2].In contrast to most secondary lymphoid organs, the development of NALT initiates postnatally [7][8][9]. Furthermore, NALT undergoes substantial changes at weaning and its structural differentiation seems to be completed 6 wk after birth indicating that NALT development might be influenced by environmental stimuli [7]. The conventional model of secondary lymphoid organ development presumes the interplay between stromal organizer cells and CD45 receptors CXCR5 and CCR7. NALT development is initiated independently of the majority of factors known to be involved in the interaction of stromal organizer and LTi cells, such as LTa, LTb, LTbR, TNF, TNFRp55, IL7-R, RORg, TRANCE, CXCL13, CCL19 and CCL21 [8][9][10][11], [8,9,12,13]. The only molecule identified so far and believed to be essential for the initiation of the NALT anlage formation is the transcriptional regulator ''inhibitor of DNA binding 2'' (Id2) [10]. Although LTi cells are missing in Id2 À/À mice it seems unlikely that the lack of this cell population is responsible for the absence of NALT in Id2 À/À mice as NALT develops in RORg À/À mice, which also lack LTi cells ...

A TNF-α–CCL20–CCR6 Axis Regulates Nod1-Induced B Cell Responses

“…Although Nod1 stimulation leads to an increase in LTab expression on B cells and CXCL13 release in a LT-dependent manner, LTb and CXCR5 were found to be dispensable for the observed increase of splenic B cells. Indeed, accumulation of B cells in postnatally induced lymphoid tissues such as BALT and noseassociated lymphoid tissue in response to microbial stimuli has been shown to occur in a LT-independent manner (41,42). Although in some contexts the LT pathway is required for optimal formation of splenic GC (43)(44)(45), GC formation occurs normally in the mesenteric lymph node (46), and mice deficient in LTbR only exhibit a defect in affinity maturation at low doses of Ag (47).…”

Mucosal vaccination by the intranasal route. Nose-associated lymphoid tissue (NALT)—Structure, function and species differences

“…In a very recent paper this was also documented and dendrites of DC extending into the nasal cavity were also demonstrated are showing the morphological prerequisites for antigen uptake by NALT [45].…”

Structure, Organization, and Development of the Mucosal Immune System of the Respiratory Tract

“…For example, although NALT is poorly developed in CXCR5-deficient and LTβR-deficient mice, postnatal exposures can promote the formation of PNAd-expressing HEVs and B cell follicle formation-events that are partly dependent on CD40 signaling, indicating that components of the adaptive immune response can facilitate NALT development (Krege et al, 2009). In fact, even in developmentally normal mice, exposure to nasal antigens, adjuvants, or pathogens dramatically alter the architecture of NALT-germinal centers are induced, HEVs and lymphatic vessels become more numerous, and there are changes to the number and phenotype of B cells, T cells, and DCs in NALT.…”