Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells.
OBJECTIVE
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-2R alpha, and interleukin-7R alpha, 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 alpha(E) expression, less cytotoxic activity, and higher interferon-gamma 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.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Hiroshi
H
Chinen
Katsuyoshi
K
Matsuoka
Toshiro
T
Sato
Nobuhiko
N
Kamada
Susumu
S
Okamoto
Tadakazu
T
Hisamatsu
Taku
T
Kobayashi
Hirotoshi
H
Hasegawa
Akira
A
Sugita
Fukunori
F
Kinjo
Jiro
J
Fujita
Toshifumi
T
Hibi
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D053687:Adult Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D016130:Immunophenotyping; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D039001:Integrin alpha Chains / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097802:CD83 Antigen; D000099232:Proto-Oncogene Protein Spi-1
D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D019002:CD56 Antigen; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D051797:Inhibitor of Differentiation Protein 2; D039001:Integrin alpha Chains; D007371:Interferon-gamma; D053645:Interleukin-2 Receptor alpha Subunit; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; D063268:Sialic Acid Binding Ig-like Lectin 3; D015534:Trans-Activators; D014157:Transcription Factors; D000097802:CD83 Antigen; D000099232:Proto-Oncogene Protein Spi-1; C571163:CD33 protein, human; C497450:ID2 protein, human; C091367:alpha E integrins; C415350:interleukin-7 receptor, alpha chain; C076877:SPIB protein, human; C498154:CD38 protein, human