Lymphoid Tissue Inducer Cells

CD45+CD4+CD3- cells are among the earliest hematopoietic cells colonizing the fetal (E13.5) LN anlagen, spleen, stomach, and intestine (Adachi et al. 1997; Mebius et al. 1997; Yoshida et al. 1999). Apart from CD4, these cells are negative for lymphoid, myeloid, or erythroid lineage markers. They can

Adhesion molecule: VCAM-1

inducer

Chemokine receptors: CXCR4, CXCR5, CCR7,...

D Chemokines: » CXCL12, CXCL13,

organizer

Chemokines: CXCL12.CXCL13, CCL21

Fig. 3 Schema of the molecular crosstalk between hematopoietic inducer and mesenchymal organizer cells. Inducer cells express LTa1p2, IL-7R, TRANCER, and TRANCE. In addition, integrins (a4p1, a4p7) and chemokine receptors (e.g., CXCR4, CXCR5, CCR7) are found on the surface of inducer cells. The IL-7R or TRANCER signaling pathway can trigger LT expression by the inducer cells. The organizer cells produce the corresponding receptors and ligands, respectively. They express LTpR, TRANCE, and IL-7 and produce adhesion molecules (VCAM-1, ICAM-1, MAdCAM-1) as well as chemokines (CXCL12, CXCL13, CCL21). Signaling via the classic NF-kB1 and NF-kB2 pathway induces gene expression of adhesion molecules and chemokines inducer

Chemokine receptors: CXCR4, CXCR5, CCR7,...

D Chemokines: » CXCL12, CXCL13,

organizer

Adhesion molecule: VCAM-1

Chemokines: CXCL12.CXCL13, CCL21

Fig. 3 Schema of the molecular crosstalk between hematopoietic inducer and mesenchymal organizer cells. Inducer cells express LTa1p2, IL-7R, TRANCER, and TRANCE. In addition, integrins (a4p1, a4p7) and chemokine receptors (e.g., CXCR4, CXCR5, CCR7) are found on the surface of inducer cells. The IL-7R or TRANCER signaling pathway can trigger LT expression by the inducer cells. The organizer cells produce the corresponding receptors and ligands, respectively. They express LTpR, TRANCE, and IL-7 and produce adhesion molecules (VCAM-1, ICAM-1, MAdCAM-1) as well as chemokines (CXCL12, CXCL13, CCL21). Signaling via the classic NF-kB1 and NF-kB2 pathway induces gene expression of adhesion molecules and chemokines be generated from a fetal liver cell subset expressing IL-7 receptor a (IL-7Ra, CD127) and a4ß7 integrin (Mebius et al. 2001; Yoshida et al. 2001). IL-7Ra+ progenitor cells colonize peripheral sites before they start to express CD4, as both IL-7Ra+CD4+ and IL-7Ra+CD4- cells are found in developing lymphoid organs (Yoshida et al. 1999). We and others have shown that fetal or neonatal CD45+CD4+CD3- cells adoptively transferred into PP-deficient mice are able to restore PP and nasopharynx-associated lymphoid tissue (NALT) development (Finke et al. 2002; Fukuyama et al. 2002). Moreover, in mice, which are unable to generate these cells during development, PPs, LNs, and NALT are not formed (Eberl et al. 2004; Sun et al. 2000; Yokota et al. 1999) (see also Sect. 3.2). The normal splenic architecture in these mutant mice demonstrates thatlymphoid tissue inducer cells are not involved in splenic T/B segregation or marginal zone development. Nishikawa and colleagues have termed CD45+CD4+CD3- cells inducer cells collaborating with mesenchymal organizer cells in LN and PP development (Nishikawa et al. 2003) (Fig. 3). Inducer cells express a4ß1 and a4ß7 integrin but are negative for L-selectin (Finke et al. 2002; Mebius et al. 1998). The firm adhesion of inducer and organizer cells needs the activation of a4ß 1 integrin expressed by the inducer cells via an "inside-out" signal (Finke et al. 2002). Inducer cells express Lía ß2, tumor necrosis factor (TNF)-related activation-induced cytokine receptor (TRANCER, RANK, OPG, TNFRSF11A), TRANCE (RANKL), IL-7Ra, and various chemokine receptors (e.g. CXCR4, CXCR5, and CCR7) (for review, see Finke 2005). LTaß expression by the inducer cells is critical for the formation of clusters of both CD45+CD4+CD3- inducer and VCAM-1+ organizer cells (see also Sect. 4.1). The engagement of IL-7R or, alternatively, TRANCER plays an important role in lymphoid organ development, as both signaling pathways stimulate the production of membrane LTai ß2 by the inducer cells.

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