Cooperating Mechanisms of CXCR5 and CCR7 in Development and Organization of Secondary Lymphoid Organs

Abstract

Homeostatic chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer's patches depends on the recruitment of CD3− CD4+ interleukin (IL)-7Rαhi cells to sites of future organ development. CD3− CD4+ IL-7Rαhi cells express the chemokine receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5−/− CCR7−/− double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both receptors in secondary lymphoid organ development. We demonstrate that CD3− CD4+ IL-7Rαhi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5−/− CCR7−/− mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5−/− CCR7−/− mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization.

Distinct Developmental Requirements for Isolated Lymphoid Follicle Formation in the Small and Large Intestine

“…23 Intestinal tissue from RANKL Ϫ/Ϫ mice and controls was stained with antibodies to CXCL13. In control mice, Figure 3.…”

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

“…CCL21 and CXCL13 are ligands for CCR7 and CXCR5 (expressed by B cells), respectively, and are secreted by mesenchymal cells in the early developing lymph node to drive lymphoid tissue formation through the attraction of CD3ε − CD4 + IL-7Rα hi CCR7 + and CXCR5 + lymphoid tissue inducer cells [62,66]. The 3D organization of the lymph node is also driven and maintained by these cytokines; FRCs of the T cell zone express CCL21 and CCL19, which guide the interactions between CCR7 + T cells and APCs, while follicular dendritic cells express CXCL13 to define and maintain zones of CXCR5 + B cells [67].…”

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

“…Although the cooperative function and reciprocal distribution of CXCR5 and CCR7 ligands in secondary lymphoid organ embryogenesis and post-natal life have been documented [1,9], no data are currently available about the mutual distribution of CCL21-and CXCL13-producing cells under inflammatory conditions and in the developing synovial lymphoid tissue. To address this point, we performed immunohistochemistry (IHC) and in situ hybridization (ISH) for CCL21 on sections sequential to those stained for CXCL13.…”

“…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].…”