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

doi:10.1053/j.gastro.2007.05.017

Gastroenterology

Volume 133, Issue 2, August 2007, Pages 559-573

https://doi.org/10.1053/j.gastro.2007.05.017 Get rights and content

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.

Section snippets

Tissue Samples

Normal intestinal mucosa and MLN were obtained from macroscopically and microscopically unaffected areas of patients with colon cancer. Intestinal mucosa also was obtained from surgically resected specimens from patients with CD or ulcerative colitis (UC), diagnosed on the basis of clinical, radiographic, endoscopic, and histologic findings, according to established criteria.20, 21 In all samples from patients with CD or UC, the degree of inflammation was histologically moderate to severe. All

Presence of Non–Cluster-Forming Lineage Markers (lin)^– c-kit⁺ Lymphocytes in the Human Adult Intestine

We first tried to identify c-kit⁺ cells in the human adult intestine by immunohistochemistry. We could not find any c-kit⁺ cell clusters such as murine CP cells; however, we found a considerable number of c-kit⁺ cells scattered in the intraepithelial space, lamina propria, and submucosal layers of both the ileum and colon (Figure 1A and B). The c-kit expression on IELs was dimmer than that on LPMCs (Figure 1B and I). Furthermore, the c-kit⁺ IELs were found only in the intraepithelial space of

Discussion

The sites of NK cell development in adults are understood poorly.40, 48 Although T/NKPs have been identified only in fetal tissues, the bone marrow is presumed to be the main site of NK cell generation in adults.40, 48 In this study, we have shown that lin^– c-kit⁺ cells in human adult intestine could differentiate into c-kit^dim cells, which express CD56 during in vitro culture, suggesting that these cells are NK cell precursors. Moreover, further analysis showed that in vitro differentiated

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: Supported in part by grants-in-aid from the Japanese Ministry of Education, Culture and Science, the Japanese Ministry of Health, Labor and Welfare, Keio University and Keio Medical Foundation, Tokyo, Japan.

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Basic–alimentary tractLamina Propria c-kit+ Immune Precursors Reside in Human Adult Intestine and Differentiate Into Natural Killer Cells

Section snippets

Tissue Samples

Presence of Non–Cluster-Forming Lineage Markers (lin)– c-kit+ Lymphocytes in the Human Adult Intestine

Discussion

Cell

Cell

Immunity

Immunity

Immunity

Blood

Blood

Blood

Blood

Gastroenterology

Blood

Immunity

Blood

Immunol Lett

Immunity

A clonogenic common myeloid progenitor that gives rise to all myeloid lineages

Nature

Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes

J Exp Med

Commitment of common T/Natural killer (NK) progenitors to unipotent T and NK progenitors in the murine fetal thymus revealed by a single progenitor assay

J Exp Med

IL-7 receptor alpha+ CD3(-) cells in the embryonic intestine induces the organizing center of Peyer’s patches

Int Immunol

Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop

J Exp Med

Generation of intestinal T cells from progenitors residing in gut cryptopatches

Science

Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells

Science

Extrathymic T cell differentiation in the human intestine early in life

J Immunol

Phenotypic characterization of CD3-7+ cells in developing human intestine and an analysis of their ability to differentiate into T cells

J Immunol

Intestinal alpha beta T cells differentiate and rearrange antigen receptor genes in situ in the human infant

J Immunol

Extrathymic TCR gene rearrangement in human small intestine: identification of new splice forms of recombination activating gene-1 mRNA with selective tissue expression

J Immunol

Human natural killer cell committed thymocytes and their relation to the T cell lineage

J Exp Med

Classification of inflammatory bowel disease

Scand J Gastroenterol Suppl

Incidence of inflammatory bowel disease in northern France (1988–1990)

Gut

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

Presence of Non–Cluster-Forming Lineage Markers (lin)^– c-kit⁺ Lymphocytes in the Human Adult Intestine