Molecular Basis for Hematopoietic/Mesenchymal Interaction during Initiation of Peyer's Patch Organogenesis

Abstract

Mice deficient in lymphotoxin β receptor (LTβR) or interleukin 7 receptor α (IL-7Rα) lack Peyer's patches (PPs). Deficiency in CXC chemokine receptor 5 (CXCR5) also severely affects the development of PPs. A molecular network involving these three signaling pathways has been implicated in PP organogenesis, but it remains unclear how they are connected during this process. We have shown that PP organogenesis is initiated at sites containing IL-7Rα+ lymphoid cells and vascular cell adhesion molecule (VCAM)-1/intercellular adhesion molecule (ICAM)-1 expressing nonlymphoid elements. Here we characterize these lymphoid and nonlymphoid components in terms of chemokine signals. The lymphoid population expresses CXCR5 and has a strong chemotactic response to B lymphocyte chemoattractant (BLC). Importantly, chemokines produced by VCAM-1+ICAM-1+ nonlymphoid cells mediate the recruitment of lymphoid cells. Furthermore, we show that these VCAM-1+ICAM-1+ cells are mesenchymal cells that are activated by lymphoid cells through the LTβR to express adhesion molecules and chemokines. Thus, promotion of PP development relies on mutual interaction between mesenchymal and lymphoid cells.

Intestinal Cryptopatch Formation in Mice Requires Lymphotoxin α and the Lymphotoxin β Receptor

“…The fetal intestinal stromal cells that are engaged by lymphoid tissue inducer cells during the earliest stages of PP development express the VCAM-1 and ICAM-1 adhesion molecules (20). Stimulation of the LT␤R on the stromal cells by membrane bound LT␣ 1 ␤ 2 on the inducer cells is a pivotal initial signal driving organogenesis of PP and lymph nodes (20). LT␣ expression by hemopoietic cells and LT␤R expression by stromal cells are also required for the development of ILF (14).…”

“…Lymphoid tissue inducer cells are CD3 Ϫ CD4 ϩ CD45 ϩ cells that also express the t isoform of the ROR␥ transcription factor (24,25). The fetal intestinal stromal cells that are engaged by lymphoid tissue inducer cells during the earliest stages of PP development express the VCAM-1 and ICAM-1 adhesion molecules (20). Stimulation of the LT␤R on the stromal cells by membrane bound LT␣ 1 ␤ 2 on the inducer cells is a pivotal initial signal driving organogenesis of PP and lymph nodes (20).…”

“…These VCAM-1 ϩ clusters, which express LT␤R, are colonized by LT␣-expressing CD3-CD4 ϩ IL-7R␣ ϩ inducer cells at around E16.5-E17.0 (19,20). LT␣ Ϫ/Ϫ and wild-type mice treated with LT␤RIg fusion protein during embryonic development do not form these VCAM-1 ϩ organizing centers and completely lack PP (5, 6).…”

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].…”

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

“…progenitors and pro-T cells in adult animals (26), and stimulation of IL-7Ra induces expression of LTa 1 b 2 in IL-7Ra + c-Kit + progenitors (42). In this study, the generation and macroscopic analysis of IL-7Ra-cre;LTb F/F mice found them to phenocopy Krt-5-cre;LTb F/F mice (Fig.…”