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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TCR-beta gene rearrangement or expression is necessary and sufficient for the progression of early alpha beta thymocyte differentiation from the CD3-CD4-CD8- triple negative (TN)3 to the CD4+CD8+ double positive stage. The onset of TCR-beta rearrangement is currently thought to occur gradually. Some thymocytes were reported to be rearranged at the earliest (CD44+CD25-) TN stage, whereas other thymocytes did not initiate TCR-beta rearrangement until the latest (CD44-CD25-) TN stage. Here, we have isolated subsets of TN thymocytes on the basis of surface expression of CD44 and CD25, with c-kit as an additional marker. We present a revised model of early T cell development in which TCR-beta and TCR-gamma rearrangements occur abruptly, at the CD44lowCD25+ c-kitlowTN stage. A high level of c-kit expression defines pro-T cells which have not yet rearranged their TCR genes. Germ-line TCR-beta transcripts, and transcripts of recombination activating genes (RAG)-1 and 2, are detected before TCR-beta gene rearrangement. Analyses of TN thymocytes of RAG-1 mutant mice, and of various TCR mutant and TCR transgenic RAG-1 mutant mice, indicate the existence of a control point at the CD44-CD25+TN stage at which cells expressing a productively rearranged TCR-beta chain are selected for further differentiation.
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PMID:Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation. 751 23

Interactions between stem cell factor (SCF) and its receptor, c-Kit, are important for development of hematopoietic, melanocytes, and germ cells. T lymphocytes appeared normal in c-Kit (W/Wv) or SCF (SI/SId) mutant mice, except for those residing within the intestinal epithelium, the intraepithelial lymphocytes (IEL). Normally, IEL are composed of equal numbers of cells with alpha beta or gamma delta T cell receptors. In mutant mice, beginning at 6-8 weeks of age, the number of gamma delta IEL decreased, whereas alpha beta IEL increased. The latter was due largely to an increased CD4+ CD8+ TCR alpha beta subset, suggesting that these cells may be intermediates in the alpha beta IEL lineage. c-Kit or SCF was expressed by IEL or intestinal epithelial cells, respectively, indicating a potential for direct intercellular interaction. This possibility was supported by reconstitution studies that demonstrated that c-Kit mutations directly affected IEL. Thus, SCF-c-Kit interactions are important for homeostasis of the intestinal immune compartment.
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PMID:Interactions between stem cell factor and c-Kit are required for intestinal immune system homeostasis. 753 19

Immature hemopoietic cell lines were established by transforming fetal thymocytes in vitro with a ts mutant of Abelson murine leukemia virus. They are positive for c-kit and IL-2R alpha but negative for lineage specific markers. Their TCR and Ig heavy chain genes are in germline configuration, and are expressed as germline gene transcripts. When these cell lines were stimulated in vitro with IL-1 their morphology changed into that of typical macrophages (M phi). Subsequent analysis of a particular clone, which displayed the morphological change at the highest efficiency among established cell lines, indicated that the clone possesses the capacity to differentiate into I-A-M phi capable of secreting several cytokines, and supporting the proliferation of fetal and adult thymocytes in vitro. If their surface markers are considered, their normal counterparts would be present in a minor subset of CD4-CD8- double-negative cells in the thymus in early development. The results raise the possibility that the thymic organ at an early stage of development stores immature hemopoietic cells capable of differentiating into a non-T lineage constituting the thymic stromal elements.
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PMID:The fetal thymus stores immature hemopoietic cells capable of differentiating into non-T lineage cells constituting the thymus stromal element. 831 23

We have subdivided mouse CD4-CD8-CD3- triple-negative (TN) thymocytes into four subsets based upon expression of CD44 and CD25, including CD44+CD25-, CD44+CD25+, CD44-CD25+ and CD44-CD25-. Characterization of these cells revealed several features distinct to each subset, in particular the expression of high levels of c-kit (the receptor for stem cell factor) by CD44+CD25-TN and CD44+CD25+TN but not by CD44-CD25+TN and CD44-CD25-TN. The CD44+CD25+TN subset also included the IL-7 and stem cell factor-responsive cells, whereas only minimal responsiveness was observed by the CD44- populations. These subsets also showed differential cytokine production potential (CD44+CD25- > CD44+CD25+ > CD44-CD25+ > CD44-CD25-) after stimulation with calcium ionophore, PMA and IL-1. The repopulation potential of these subsets in 2-deoxyguanosine-treated fetal thymic lobes supports the following maturation sequence: CD44+CD25- -->CD44+CD25+ -->CD44-CD25+ -->CD44-CD25-. Furthermore, the sequence of progression from CD44+CD25+ to CD44-CD25+ cells was confirmed by their TCR beta-chain gene configuration. The former population exhibits germ-line TCR beta-chain configuration, whereas the latter subset shows a rearranged pattern.
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PMID:A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. 838 91

Thymocytes of mice deficient in the recombinase-activating gene (RAG)-1 or RAG-2 cannot express and receive signals through the pre-TCR. As a result, thymocyte development in these mice terminates at the CD4/8 double negative (DN), IL-2R-alpha-positive stage. Nevertheless, RAG-deficient DN thymocytes express functional CD3 complexes and can therefore be induced by anti-CD3 epsilon mAb to mature to the CD4+8+ double positive stage. In the present paper we demonstrate that the peripheral lymphoid organs (lymph nodes, spleen) and peripheral blood of RAG-deficient mice harbor an immature T cell population which, similar to RAG-deficient DN thymocytes, contains high levels of cytoplasmic CD3 epsilon and responds to anti-CD3 epsilon mAb in vivo. With respect to surface phenotype (Thy1.2+, PgP-1+, HSA+, Fc gamma RII/III-, IL-2R-alpha-, c-kit-), these cells are similar to intermediate stage RAG-deficient DN thymocytes. Moreover, they express mRNA for pre-TCR-alpha and for the nondeleted RAG. Following injection of anti-CD3 epsilon mAb, these cells proliferate, down-regulate heat stable Ag and PgP-1, and partially differentiate to CD4+ and CD8+ double positive and single positive cells. The induced population displays a mixed phenotype, between that of immature thymocytes and lymph node T cells in normal mice. Induction is successful in thymectomized RAG-deficient mice, suggesting that it occurs in the periphery. However, after thymectomy, inducible cells disappear with an approximate half-life of 10 to 14 days. We suggest that DN thymocytes can emigrate and repopulate peripheral lymphoid organs of RAG-deficient mice. These cells respond to CD3 signaling by aberrant maturation, possibly due to the inappropriate microenvironment of peripheral lymphoid organs.
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PMID:Immature T cells in peripheral lymphoid organs of recombinase-activating gene-1/-2-deficient mice. Thymus dependence and responsiveness to anti-CD3 epsilon antibody. 856 35

Human natural killer (NK) cells are bone marrow (BM)-derived CD2+CD16+CD56+ large granular lymphocytes (LGL) that lack CD3 yet contain the T-cell receptor zeta-chain (zeta-TCR). NK cells provide requisite interferon-gamma (IFN-gamma) during the early stages of infection in several experimental animal models. A number of studies have shown that human CD3-CD56+ NK cells can be obtained from BM-derived CD34+ hematopoietic progenitor cells (HPCs) cultured in the presence of interleukin-2 (IL-2) and an allogeneic feeder cell layer, or IL-2 and other hematopoietic growth factors such as the c-kit ligand (KL). The failure to detect the IL-2 gene product within the BM stroma and the presence of NK cells in IL-2-deficient mice suggested that cytokines other than IL-2 may participate in NK cell differentiation from HPCs in vivo. IL-15 is a cytokine which, while lacking any sequence homology in IL-2, can activate cells via the IL-2 receptor. Here we show that human BM stromal cells express the IL-15 transcript, and supernatants from long-term BM stromal cell cultures contain IL-15 protein. In vitro, CD3-CD56+ NK cells can be obtained from 21-day cultures of CD34+ HPCs supplemented with IL-15 in the absence of IL-2, stromal cells, or other cytokines. The addition of the KL to these cultures had no effect on the differentiation of the CD3-CD56+ cytotoxic effector cells, but greatly enhanced their expansion. The majority of these cells lack CD2 and CD16, but do express zeta-TCR. Similar to NK cells found in peripheral blood, the CD2-CD16-CD56+ NK cells grown in the presence of IL-15 were found to be potent producers of IFN-gamma in response to monocyte-derived cytokines. Thus IL-15, like KL, appears to be produced by BM stromal cells. IL-15 can induce CD34+ HPCs to differentiate into CD3-CD56+ NK cells, and KL can amplify this. Therefore, IL-15 may be a physiologically relevant ligand for NK cell differentiation in vivo.
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PMID:Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. 863 78

Positive selection of T cells begins with TCR alpha beta lo thymic progenitors. Here, we show that the most efficient TCRlo progenitors are c-kit+ with intermediate levels of CD4 and CD8 (DPint). Positive selection of DPint TCRlo c-kit+ cells results in TCRmed CD69+ c-kit+ transitional intermediates that show increased TCRV beta frequencies to selecting superantigen (SAg) that are committed to the CD4 or CD8 pathway. The cells on the c-kit+ maturation pathway maintain Bcl-2 expression. Most DPint c-kit+ progenitors fail positive selection, and become DPhi c-kit- cells that lose Bcl-2 expression. Some DPhi c-kit blast cells can be salvaged to produce mature single-positive (SP) cells. DPint c-kit+ maturation to SP cells can occur in <12 hr in vitro on thymic stromal monolayers.
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PMID:The c-kit+ maturation pathway in mouse thymic T cell development: lineages and selection. 876 78

We have revealed that about one and a half thousand tiny clusters, filled with one thousand closely packed lymphocytes, can be found throughout the murine small and large intestinal mucosa. They are located in crypt lamina propria (cryptopatches; CP) and can be first detected at 14-17 d after birth. A large fraction of lymphocytes in CP expresses c-kit, IL-7R, Thy1 and a lymphocyte function-associated antigen, LFA-1, whereas most of them remain CD3-, TCR alpha beta-, TCR gamma delta-, sIgM-, and B220-. The population size of IL-2R alpha+, HSA+ and Pgp-1+ subsets is variable (20-50%) and the composition of CD8+, Ly-1+, and CD4+ subsets is smaller but also variable (3-20%). In the small intestine, CP do not contain cells undergoing apoptosis nor cells bearing RAG-1 molecules, but do contain dendritic stromal cells bearing CD11c/CD18 molecules. The frequency of DNA replicating cells in CP is higher than that in Peyer's patches (PP), is lower than that in the thymic cortex and is almost comparable with that in the thymic medulla. The numbers of CP remain the same in aged mice (> 114 wk) but double after estrogen treatment even though the thymi are attenuated sharply in both conditions. Thus, with respect to histogenesis, lymphocyte composition and tissue level of cellular behavior, neither PP, isolated lymphoid follicles, peripheral LNs, nor thymus are identical with CP. Finally, CP are virtually absent in lamina propria of IL-7R-deficient mice that display a profound reduction in thymic and peripheral lymphoid cellularity. By contrast, CP are present in germ-free mice and in athymic (nu/nu), SCID, TCR beta x delta-/-, RAG-2-/-, PP-deficient (aly/aly), stem cell factor (Sl/Sld) and c-kit (W/Wv) mutant mice. Taking all of these results together, CP are the first identification of gut-associated murine lymphoid tissues where the generation of IL-7-dependent lympho-hematopoietic progenitors for T and/or B cell descendants may start to take place at the age of commencement of weaning.
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PMID:Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. 887 90

In order to determine whether the cells immigrating into the thymus have been committed to the T cell lineage, we examined the gene expression of the TCR complex in fetal thymus (FT) and fetal liver (FL) precursors. We previously showed that c-kit bright-positive, Pgp-1 bright-positive and lineage markers negative fetal thymocytes (c-kit+ FT cells) are the most immature cells which do not undergo gene rearrangement of the TCR beta chain. In this study, we demonstrated that the gene rearrangement of TCR gamma as well as beta chains does not occur in c-kit+ FT cells, but that the germline transcript of their TCR beta was found in J-C regions. The TCR beta gene was demethylated in c-kit+ FT cells. CD3 gamma, delta and epsilon subunit genes were also expressed at the mRNA levels in c-kit+ FT cells, but cytoplasmic protein staining divided them into two populations: cytoplasmic CD3 epsilon positive and negative cells. These features were not observed in c-kit+ FL cells. Moreover, Ly-1 expression was found on c-kit+ FT cells but not on c-kit+ FL cells. These results indicate that DNA alteration on the TCR beta gene initiates with other phenotype expression determining the T cell lineage in the thymus prior to TCR gene rearrangement.
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PMID:Transcription and demethylation of TCR beta gene initiate prior to the gene rearrangement in c-kit+ thymocytes with CD3 expression: evidence of T cell commitment in the thymus. 892 26

To analyze the early development of T cell precursors in the absence of TCR gene rearrangement, recombinase-activating gene-deficient (RAG-2 -/-) thymocytes were compared with thymocytes from SCID mice on the C.B-17 (BALB) and B6 genetic backgrounds. RAG-2 -/- thymocytes accumulate as quiescent cells with a heat-stable Ag (HSA)-positive CD25+ CD44- c-kit(low) phenotype, resembling normal cells just before selection for functional TCR beta-chain expression. CD44 and c-kit progressively down-regulate in the HSA+ subset, providing a background-independent and TCR-independent developmental clock. On this basis, compared with RAG-2 -/- thymocytes, SCID thymocytes 1) arrest at more heterogeneous, and generally earlier, stages; 2) accumulate to lower overall cell numbers; and 3) maintain higher populations of cycling and activated G1 cells, showing both increased responsiveness and increased cell death. B6-SCID thymocytes appear to die particularly early. Low levels of Fas were observed on "advanced" HSA+ SCID thymocytes but not on any RAG-2 -/- thymocytes, suggesting a potential difference in activation state or mechanism of death. In both RAG-2 -/- and SCID thymocytes, there are also two discrete subsets of HSA(low) CD25- CD44+ c-kit+ cells: a Sca-1+ CD44++ CD122- NK1.1- putative progenitor subset and an NK-like Sca-1- CD44+(+) CD122+ NK1.1+ subset. The absolute cell numbers in these HSA(low) subsets and the extent of NK cell differentiation, measured by perforin expression, are nearly constant in all the mutant strains analyzed, in contrast to the HSA+ CD25+ population, which was expanded in the RAG-2 -/-. Thus, the SCID thymocytes appear to undergo a normal generation but a premature death as compared with the RAG-2 -/- thymocytes.
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PMID:Different developmental arrest points in RAG-2 -/- and SCID thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement. 912 63


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