Presumptive Lymph Node Organizers are Differentially Represented in Developing Mesenteric and Peripheral Nodes

Abstract

During murine embryogenesis, the formation of Peyer’s patches (PPs) is initiated by CD45+CD4+CD3− lymphoid tissue inducers that trigger adhesion molecule expression and specific chemokine production from an organizing stromal cell population through ligation of the lymphotoxin-β receptor. However, the steps involved in the development of lymph nodes (LNs) are less clear than those of PPs, and the characteristics of the organizing cells within the LN anlagen have yet to be documented. In this study, we show for the first time that the early anlage is bordered by an endothelial layer that retains a mixed lymphatic and blood vascular phenotype up to embryonic day 16.5. This in turn encompasses CD45+CD4+CD3− cells interspersed with ICAM-1/VCAM-1/mucosal addressin cell adhesion molecule-1, lymphotoxin-β receptor-positive, chemokine-producing cells analogous to the organizing population previously observed in PPs. Moreover, these LN organizers also express the TNF family member, TRANCE. Lastly, we show that the ICAM-1/VCAM-1/mucosal addressin cell adhesion molecule-1 cells present in peripheral and mesenteric LN form two discrete populations expressing either intermediate or high levels of these adhesion molecules but that the former population is specifically reduced in PLN. These findings provide a possible explanation for the well-known differences in developmental requirements for nodes at peripheral or mesenteric locations.

Cellular Interactions in Lymph Node Development

“…This is supported by the fact that, upon transgenic overexpression of TRANCE in hemopoietic cells of the TRANCE Ϫ/Ϫ mice, numbers of LTi cells increase, resulting in the formation of several lymph nodes (16). During embryonic development, TRANCE expression is found on LTi cells, but most notably on stromal cells within the developing lymph nodes (2,16). Local production of TRANCE, together with the findings that PPs develop normally in the absence of TRANCE, implies that TRANCE acts locally by either attracting or differentiating LTi cells.…”

“…3). First, the mesenchymal cells differentiate toward stromal cells that produce TRANCE (2), and perhaps at this point are also induced to express LT␤R and TNFR. Second, triggering of LT␤R leads to the up-regulation of adhesion molecules, such as VCAM-1, and the production of chemokines.…”

“…T he successful formation of lymph nodes depends on interactions between lymphotoxin (LT)␤R 2 -expressing organizing cells and LT␣ 1 ␤ 2 -expressing inducer cells (1)(2)(3)(4). The inducer cells are believed to be hemopoietic cells that express the IL-7R␣ chain and CD4, but lack CD3.…”

“…The inducer cells are believed to be hemopoietic cells that express the IL-7R␣ chain and CD4, but lack CD3. These CD45 ϩ CD4 ϩ CD3 Ϫ lymphoid tissue inducer (LTi) cells are among the earliest cells to be found within the embryonic lymph node anlagen (1,2,5), and were shown to be the inducer cells for Peyer's patches (PPs) and the nasal-associated lymphoid tissue ( Fig. 1) (6,7).…”

Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis

“…They have been implicated in lymphocyte recruitment from the bloodstream [2][3][4], the structural compartmentalization of T-B microdomains [5][6][7] and T-B cell interactions within the tissue [8]. Recent studies have demonstrated that the same chemokines (CK) are required for the embryonic development and organization of the majority of secondary lymphoid organs [9], being produced by a subset of mesenchymal cells (VCAM-1 + LTbR + , "organizers") in the early lymphoid anlagen [10,11]. It has been suggested that these CK contribute to the clustering of the earliest wave of hematopoietic cells (CD3 -CD4 + LTb + , "inducers"), preceding peripheral node addressin (PNAd) + high endothelial venule (HEV) formation, T-B lymphocyte compartmentalization and follicular dendritic cell (FDC) network development [12].…”