Kit Ligand and Il7 Differentially Regulate Peyer’s Patch and Lymph Node Development

Abstract

Hematopoietic lymphoid tissue inducer (LTi) cells initiate lymph node (LN) and Peyer’s patch (PP) development during fetal life by inducing the differentiation of mesenchymal organizer cells. The growth factor signals underlying LTi cell development and LN and PP organogenesis remain poorly understood. LTi cells express the Il7r and the receptor tyrosine kinase Kit, whereas organizer cells express their cognate ligands. To determine the relative significance of Il7 and Kit signaling in LTi cell homeostasis and PP and LN development, we have analyzed mice deficient for Kit (KitW/Wv), Il7 (Il7−/−), or both (Il7−/− KitW/Wv). Unlike KitW/Wv and Il7−/− single mutants, Il7−/− KitW/Wv mice were almost devoid of LTi cells in their mesenteric LN anlage. This LTi deficiency was associated with a block in mesenchymal LN organizer cell generation and the absence of almost all LNs. In contrast, intestinal LTi cell numbers, PP organizer cell generation, and PP development were strongly affected by impaired Kit signaling, but were independent of Il7. Hence, Kit and Il7 act synergistically in LN organogenesis, whereas Kit signaling, but not Il7, critically regulates PP organogenesis and LTi cell numbers in the intestine. Consistent with these differential growth factor requirements for PP and LN development, PP organizer cells expressed higher Kitl and lower Il7 levels than did LN organizer cells. Collectively, these results demonstrate that Kit and Il7 differentially control PP and LN organogenesis through the local growth factor-driven regulation of LTi cell numbers.

Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice

“…Finally, our data suggest that Flt3L and IL-7 act on different stages of ILC development. The development of LNs and PPs depends on LTi cells (7) and is regulated by cytokines such as IL-7, SCF, and receptor activator of NF-kB ligand (29,(53)(54)(55) mice. In contrast, the lack of PPs is presumably caused by the simultaneous reduction of both LTin and LTi cell numbers in the SI of flt3l 2/2 mice.…”

“…1A). We have previously shown that IL-7 is crucial for LTi cell (45) and LN development (31) and that, in addition to IL-7, other cytokines promote intestinal LTi cell and PP development (29,31). To investigate whether Flt3L has an influence on LTi cell development, we analyzed fetal and neonatal flt3l 2/2 mice and compared them with WT and Il7 2/2 mice.…”

“…NK cells depend on IL-15 but not on IL-7 (27), which instead is crucial for ILC3s (13,(28)(29)(30) and ILC2s (15,17). In addition, we have shown that stem cell factor (SCF) (29) and thymic stromal lymphopoietin (31) are important for LTi cell development. During fetal development, LTi cells arise from CD127 + fetal liver (FL) progenitors (32,33).…”

Development of the Immune System - Early Nutrition and Consequences for Later Life

“…In addition there are differences in essential transcription factors which are necessary to develop lymph nodes or PP, like interleukin (IL) 7 and RANK (Chappaz, Gartner et al 2010). Using mice deficient for IL7 or Kit or both they showed that IL7 is important for lymph node anlagen but not for PP development whereas both Kit and Il7 are important for MLN anlagen (Chappaz, Gartner et al 2010). But growth factors needed for lymph node development still remain poorly understood.…”

Peyer’s Patch Inducer Cells Play a Leading Role in the Formation of B and T Cell Zone Architecture

“…Although LNs and PPs differ in their molecular requirements for initiating organogenesis, LTab and LTi cells that express LTab are key components regulating anlage formation, the former at the molecular level and the latter at the cellular level (13)(14)(15)(16)(17). LTi cells diverge from the lymphocyte differentiation pathway in the fetal liver (15,18), and two transcriptional regulators, Id2 and RORg, have been identified as essential for the lineage commitment of LTi cells (19)(20)(21)(22)(23).…”