IL-15 does not affect IEL development in the thymus but regulates homeostasis of putative precursors and mature CD8αα⁺ IELs in the intestine

Mice devoid of the IL-15 system lose over 90% of CD8αα ⁺ TCRαβ and TCRγδ intestinal intraepithelial lymphocytes (iIELs). Previous work revealed that IL-15Rα and IL-15 expressed by parenchymal cells, but not by bone marrow-derived cells, are required for normal CD8αα⁺ iIEL homeostasis. However, it remains unclear when and how the IL-15 system affects CD8αα ⁺ iIELs through their development. This study found that IL-15Rα is dispensable for the thymic stage of CD8αα ⁺ TCRαβ and TCRγδ iIEL development but is required for the maintenance and/or differentiation of the putative lineage marker negative precursors in the intestinal epithelium, especially for the most mature CD8 single positive subset. Moreover, the IL-15 system directly supports the survival of mature CD8αα⁺ iIEL in vivo. Taken together, this study suggests that regulation of CD8αα⁺ iIEL homeostasis by the IL-15 system does not occur in the thymus but involves mature cells and putative precursors in the intestine.