Development of mammalian secondary lymphoid tissue is a programmed process governed by the sophisticated cytokine network, especially TNF family cytokines such as RANKL and Lymphotoxins (LTs). Lymphoid Tissue inducer (LTi) cell is a member of group 3 innate lymphoid cells (ILC3). In the absence of LTi cells, development of all the secondary lymphoid tissue is impaired.
Previous studies showed essential role of RANKL on the development of lymph node (LN) but not on the development of Gut-Associated Lymphoid Tissues (GALTs). However, the difference in the usage of RANKL signal during organ development between LNs and GALTs remained to be elucidated.
In this study, we first identified RANKL-expressing mesenchymal cells in both LNs and GALTs using RANKL-reporter mouse system. We also proved that mesenchymal stromal cell play predominant role as a source of RANKL during LN formation. We further proved that RANK, a receptor for RANKL on LN-resident LTi cells transduced signals essential for LTi cell maturation. On the other hand, GALT-resident LTi cells did not express RANK. Taken together, LTi cell worked as a “hub” that integrated mesenchymal cell-derived RANKL in the LN but not in the GALT anlagen.
Careful observation of RANK-deficient mice provided us another aspect of GALT development. GALTs of RANKL deficient mice harbored less B cells and produced lower amount of IgA than that of the control. This phenotype was due to impaired development of Microfold cell (M cell), a subset of epithelial cell specialized for antigen uptake into the GALT. The actual source of RANKL required for M cell development was a subset of mesenchymal cell localized sub-epithelial region of GALTs, namely M cell inducer (MCi) cells.