Inflammation, a prototype for organogenesis of the lymphopoietic/hematopoietic system

The molecular and cellular events that initiate the formation of T and B cell areas in developing lymph nodes are poorly understood. In this study we show that formation of the lymphoid architecture in murine neonatal lymph nodes evolves through a series of distinct stages. The initial segregation of T and B cells is regulated in a CXCL13-independent manner, characterized by the localization of B cells in a ring-like pattern in the outer cortex on day 4. However, during this CXCL13-independent phase of lymph node modeling, CXCL13 is expressed and regulated in a lymphotoxin-α1β2 (LTα1β2)-dependent manner. Surprisingly, neonatal B cells are unable to respond to this chemokine and also lack surface LTα1β2 expression. At this time, CD45+CD4+CD3− cells are the predominant LTα1β2-expressing cells and are also capable of responding to CXCL13. From day 4 on, architectural changes become CXCL13 dependent, and B cells become fully CXCL13 responsive, express LTα1β2, and cluster in anatomically distinct follicles. Because the initial induction of CXCL13 is dependent on LTα1β2, a role for CD45+CD4+CD3− cells in inducing chemokine expression in the developing lymph nodes is proposed and, as such, a role in initiation of the shaping of the microenvironment.

Section: Discussionmentioning

confidence: 99%

Initiation of Cellular Organization in Lymph Nodes Is Regulated by Non-B Cell-Derived Signals and Is Not Dependent on CXC Chemokine Ligand 13

Cupedo¹,

Lund

Ngo

et al. 2004

“…Studies on PP development have led to a model whereby a hemopoietic "inducer" cell displays surface LT in response to IL-7 signaling. The LT-positive cell triggers LT␤R-positive mesenchymal cells to become a VCAM ϩ /ICAM ϩ "organizer" (4,13,25). The genetic lack of LT blocks PP development at the earliest detectable stage, i.e., formation of the VCAM/ICAM ϩ anlage at E16; however, it has not been formally proven that a hemopoietic cell delivers this LT signal at the early stages.…”

Section: Discussionmentioning

confidence: 99%

“…The discovery that the lymphotoxin (LT) 3 system plays key roles in both embryonic and pathological lymphoid organ formation as well as in the maintenance of lymphoid architecture suggests that common mechanistic elements are being utilized in all three settings (3). There are also parallels between the signals employed in inflammatory events and Peyer's patch (PP) development (4). Thus, an analysis of ontological motifs is likely to provide novel insight into the control of architecture and cellular positioning in both the normal and inflamed adult organs.…”

mentioning

confidence: 99%

“…In contrast, considerable progress has been made in visualizing PP development by use of in situ whole-mount histological methods (4,13). Several stages in PP development can be recognized in the mouse from the initial anlage formation and expression of VCAM, to the seeding with the IL-7R ϩ , CD4 ϩ , CD3 Ϫ organizer cell and, finally, filling with mature lymphocytes.…”

mentioning

confidence: 99%

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Visualization of Lymphotoxin-β and Lymphotoxin-β Receptor Expression in Mouse Embryos

Browning

French

2002

The heteromeric lymphotoxin αβ ligand (LT) binds to the LTβ receptor (LTβR) and provides an essential trigger for lymph node (LN) development. LTβR signaling is also critical for the emergence of pathological ectopic lymph node-like structures and the maintenance of an organized splenic white pulp. To better understand the role of LT in development, the expression patterns of LTβ and LTβR mRNA were examined by in situ hybridization in the developing mouse embryo. Images of LTβ ligand expression in developing peripheral LN in the E18.5 embryo revealed a relatively early phase structure and allowed for comparative staging with LN development in rat and humans. The LTβR is expressed from E16.5 onward in respiratory, salivary, bronchial, and gastric epithelium, which may be consistent with early communication events between lymphoid elements and epithelial specialization over emerging mucosal LN. Direct comparison of mouse fetal and adult tissues by FACS analysis confirmed the elevated expression of LTBR in some embryonic epithelial layers. Therefore, surface LTBR expression may be elevated during fetal development in some epithelial layers.

“…Therefore, it is highly likely that the capacity of organizer cells to attract hemopoietic cells and orchestrate their spatial positioning during lymphoid organogenesis is a role that myofibroblasts fulfill in inflammatory lesions. In view of that, inflammatory lesions could be abridged to inducer and organizer cells, similar to the basic mechanisms of lymphoid organ development (54). In this scenario, the inducer cells would be hyperactivated lymphocytes that induce and subsequently continuously trigger myofibroblasts.…”

Section: Stromal Compartments In Inflammatory Lesionsmentioning

confidence: 96%

Cellular Interactions in Lymph Node Development

Cupedo

Mebius

2005

113

The organized accumulation of lymphocytes is a biological phenomenon used to optimize both homeostatic immune surveillance, as well as chronic responses to pathogenic stimuli. During embryonic development, circulating hemopoietic cells gather at predestined sites throughout the body, where they are subsequently arranged in T and B cell-specific areas characteristic of secondary lymphoid organs. In contrast, the body seems to harbor a limited second set of selected sites that support formation of organized lymphoid aggregates. However, these are only revealed at times of local, chronic inflammation, when so-called tertiary lymphoid structures appear. Once thought of as two distinct phenomena, recent insights suggest that highly similar networks of paracrine interactions regulate the formation of both secondary and tertiary lymphoid structures. This review will focus on these cellular interactions between organizing and inducing cell populations leading to the formation of lymph nodes or organized inflammatory infiltrates.