Lamina Propria c-kit⁺ Immune Precursors Reside in Human Adult Intestine and Differentiate Into Natural Killer Cells

Background & Aims: Recent studies have revealed that murine intestinal mucosa contains several kinds of lineage markers (lin)^- c-kit⁺ immune precursor cells. However, immune precursors in the human adult intestine have not been studied extensively. Methods: Lamina propria mononuclear cells and intraepithelial lymphocytes from surgically resected human adult intestine were examined for the surface antigen expression and cytokine profile by immunohistochemistry and flow cytometry. The transcriptional profile of these cells was analyzed by reverse-transcription polymerase chain reaction. The phenotypic and functional characterization of the in vitro differentiating cells from the precursors was examined by flow cytometry. Results: We identified lin^- c-kit⁺ cells scattered throughout lamina propria of the human adult intestine. These intestinal immune precursors expressed CD34, CD38, CD33, interleukin-2Rα, and interleukin-7Rα, and they had much more abundant expression of Id2, PU.1, SpiB1, and lymphotoxin than thymocytes. The lin^- c-kit⁺ immune precursors mainly differentiated into CD56⁺ c-kit^dim cells during in vitro culture. These in vitro differentiating cells corresponded to intestinal natural killer (NK) cells, which had distinct characteristics from their peripheral counterparts, such as CD83 and integrin α_E expression, less cytotoxic activity, and higher interferon-γ production. Furthermore, both c-kit^dim cells and NK cells were increased in lamina propria of Crohn's disease, although there was no change for peripheral blood NK cells. Conclusions: The human intestine may have the unique NK cell differentiation system, which may contribute to maintenance of immune homeostasis in the intestine.