Heterogeneity of thymic epithelial cells in promoting T-lymphocyte differentiation in vivo.

Gutierrez, José; Palacios, Ronald

doi:10.1073/pnas.88.2.642

Cited by 51 publications

(27 citation statements)

References 35 publications

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“…The Tcr b-Jbl probe (400-bp PvuII-PstI fragment), the Tcr y-J1 probe (1.2-kb AvaI-HindIII fragment), the Tcr P-Jpl probe (3.3-kb BamHI-EcoRI fragment), the Tcr P-JP2 probe (0.75-kb HindIII-EcoRI fragment) (36), the pJll probe (1.9-kb BamHI-EcoRI fragment) specific for the Ig JH gene (15), the 0.42-kb XhoI-PstI fragment of the CA1 mouse cDNA (2), and the 2.6-kb HindIII-BamHI fragment containing the kappa exon (43) were used to assess the state of Tcr and Ig genes. The PB1O A T3-y cDNA specific for mouse CD3--y (0.9-kb HindIII-EcoRI fragment) (12), the M6-BSK cDNA specific for mouse RAG-1 (1.4-kb EcoRI-EcoRI fragment), the MR2-1 cDNA specific for RAG-2 (1.0-kb PstI-PstI fragment) (28), the PuCN374 cDNA specific for the c,u Ig chain (1.3-kb BamHI-BamHI fragment) (18), the pZ183-la cDNA specific for mouse X5 (0.7-kb HindII-XhoI fragment), the pZ121 cDNA specific for mouse Vpre-B1 (0.9-kb EcoRI fragment) (14), the 0.94-kb EcoRI-BglII fragment of the MB-1 cDNA (39), the 1.1-kb PstI-PstI cDNA fragment specific for the 0-actin gene (kind gift of Susan Carson, Basel Institute for Immunology, Basel, Switzerland), and IL-la (1.9-kb BamHI-BamHI), IL-2 (1-kb XhoI-XhoI), IL-3 (0.37-kb HindIII-XbaI), IL-4 (0.3-kb RsaI-RsaI), IL-5 (0.43-kb XhoIXhoI), IL-6 (0.65-kb EcoRI-BglII), IL-7 (0.45-kb SstIHindIII) (5,40), and Steel factor (SF) (0.83-kb XhoI-XhoI) (32a) probes were used in Northern blot assays.…”

Section: Methodsmentioning

confidence: 99%

“…The tubes were centrifuged, and the cells were washed once, and diluted 1:15 in culture medium, and distributed in new six-well Costar plates. The FLS4.1 stromal cells were expanded, several aliquots were frozen (in IMDM containing 20% FCS and 14% dimethyl sulfoxide), and some cells were used to determine their phenotype by immunofluorescence staining and flow fluorocytometry (FCM) analysis (see below) before and after cell membrane permeabilization with digitonin as described earlier (5).…”

Section: Methodsmentioning

confidence: 99%

“…Isolation and analysis of nucleic acids. DNA and total RNA preparation, restriction enzyme digestions, agarose gel electrophoresis, DNA and RNA blotting, probe preparations, hybridization procedures, and autoradiography were performed as described previously (5,31,36).…”

Section: Methodsmentioning

confidence: 99%

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Fetal liver pro-B and pre-B lymphocyte clones: expression of lymphoid-specific genes, surface markers, growth requirements, colonization of the bone marrow, and generation of B lymphocytes in vivo and in vitro.

Palacios¹,

Samaridis²

1992

Mol. Cell. Biol.

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We describe here the development and characterization of the FLS4.1 stromal line derived from 15-day fetal liver of BALB/c embryos and defined culture conditions that efficiently support the cloning and long-term growth of nontransformed B-220+ 14-day fetal liver cells at two stages of B-cell development, namely, pro-B lymphocytes (immunoglobulin [Ig] genes in germ line configuration) and pre-B cells (JH-rearranged genes with both light-chain Ig genes in the germ line state). All B-cell precursor clones require recombinant interleukin-7 (rIL-7) and FLS4.1 stromal cells for continuous growth in culture, but pro-B lymphocyte clones can also proliferate in rIL-3. None proliferate in rIL-i, rIL-2, rIL-4, rIL-5, rIL-6, or leukemia inhibitory factor. FLS4.1 stromal cells synthesize mRNA for Steel factor but not for IL-1 to IL-7; all pro-B and pre-B clones express c-Kit, the receptor for Steel factor, and a c-Kit-specific antibody inhibits the enhanced proliferative response of fetal liver B-220+ B-cell precursors supported by FLS4.1 stromal cells and exogenous rIL-7 but does not affect that promoted by rIL-7 alone. Northern (RNA) blot analysis of the expression of the MB-1, A5, Vpre-B, c,u, RAG-1, and RAG-2 genes in pro-B and pre-B clones show that transcription of the MB-1 gene precedes IgH gene rearrangement and RNA synthesis from c,, RAG-1, RAG-2, A5, and Vpre-B genes. All clones at the pre-B-cell stage synthesize mRNA for c,u, RAG-1, and RAG-2 genes; transcription of the AS and Vpre-B genes seems to start after D-to-JH rearrangement in B-cell precursors, indicating that the proteins encoded by either gene are not required for B-cell progenitors to undergo D-to-JH gene rearrangement. These findings mark transcription of the MB-1 gene as one of the earliest molecular events in commitment to develop along the B-lymphocyte pathway. Indeed, both pro-B and pre-B clones can generate in vitro and in vivo B lymphocytes but not T lymphocytes; moreover, these clones do not express the CD3--y T-cell-specific gene, nor do they have rearranged y, 8, or j8 T-cell antigen receptor genes.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Fetal liver pro-B and pre-B lymphocyte clones: expression of lymphoid-specific genes, surface markers, growth requirements, colonization of the bone marrow, and generation of B lymphocytes in vivo and in vitro.

Palacios¹,

Samaridis²

1992

Mol. Cell. Biol.

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“…In order to define the potential interaction of IL-7 secreting cells in colorectal cancer and the immune system, we have examined freshly harvested cancer specimens for IL-7 mRNA expression and protein production. To this end, only a limited number of natural IL-7 sources, including bone marrowderived stromal cells or thymic epithelial cells, have been described [19]. IL-7 is a growth factor for thymocytes, supports the gowth of pre-B cells, induces proliferation, augments immune effector cell functions in CD4 þ and CD8 þ T-cells, and induces cytokine and tumouricidal activity in monocytes [20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Interleukin‐7 (IL‐7) in Colorectal Cancer: IL‐7 is Produced by Tissues from Colorectal Cancer and Promotes Preferential Expansion of Tumour Infiltrating Lymphocytes

et al. 1997

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Despite increasing survival rates for patients with colorectal cancer, additional treatment options are required, including active or passive immunotherapy for patients with metastatic disease. Freshly harvested colorectal cancer specimens and in vitro cultured colorectal cancer cell lines were examined for IL-7 protein secretion in order to examine the potential role of this cytokine in the interaction between tumour cells and the host immune system. Freshly harvested colorectal cancer specimens (21/21), or normal adjacent mucosa (3/3), as well as long-term established colorectal cancer cell lines (3/4) exhibited IL-7 mRNA expression as detected by RT-PCR and confirmed by Southern Blot analysis. Freshly harvested colorectal cancer tissue (16/18), or long-term established colorectal cancer cell lines (2/4) secreted in vitro IL-7 as detected by ELISA. In contrast, breast, pancreatic, or lung cancer cell lines, as well as several haematopoietic cancer cells lines, tested negative for IL-7 mRNA and protein. The authors tested different cytokines (IL-1b, IL-2, IL-7, or a combination of IL-1b/IL-7) in vitro for the ability to expand tumour -infiltrating T lymphocytes (TIL) from individual patients (n ¼ 9) with colorectal cancer. TIL populations were tested at day 14 after in vitro propagation for phenotypic analysis by FACS and for reactivity directed against NK and LAK sensitive target cells and autologous cancer cells as measured by cytotoxicity and cytokine release. TIL obtained from colorectal cancer lesions can be efficiently expanded in the presence of IL-7, some (3/9) of which appear to exhibit autologous tumour recognition as measured by cytolytic effector functions and by detection of IFNg and TNFa release. Detection of IL-7 mRNA expression in colorectal cancer, in normal mucosa adjacent to tumour, as well as the ability of colorectal cancer tissue to secrete IL-7, raises new questions about the biology of the host / tumour interactions in colorectal cancer.

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“…IL-7 is produced by stromal cell populations throughout the body 15 and is produced in high concentrations by thymic epithelium. 16,17 Animal models have shown that IL-7 is required for early thymocyte development and supraphysiologic doses of IL-7 enhance thymopoiesis. 13,[18][19][20] Thus, IL-7 potentially holds promise as an immunorestorative agent in the setting of allogeneic BMT.…”

Section: Introductionmentioning

confidence: 99%

Interleukin 7 worsens graft-versus-host disease

Sinha

Fry

Fowler

et al. 2002

Blood

110

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Impaired immune reconstitution has moved to the forefront of clinical problems limiting progress in allogeneic bone marrow transplantation (BMT). The identification of therapies that can enhance immune reconstitution by increasing thymopoiesis is critical to solving this problem. Interleukin 7 (IL-7) is the most potent thymopoietic cytokine identified thus far. To study the effects of IL-7 on immune reconstitution and graftversus-host disease (GVHD) following allogeneic BMT, we administered recombinant human IL-7 (rhIL-7) in a murine parent into an F1 model. Results showed that rhIL-7 therapy lowered the "threshold" T-cell dose required to induce both clinical signs of GVHD as well as lethal GVHD. Histologic analysis of GVHD target tissues revealed that rhIL-7 increased the degree of inflammation and tissue damage observed at all T-cell doses studied, but did not change the pattern of organs affected or the histologic appearance of the GVHD within target organs. In addition, we evaluated the capacity for rhIL-7 to enhance thymopoiesis in the setting of allogeneic T cell-depleted (TCD) and T-cell-replete BMT. We observed that rhIL-7 therapy enhanced thymic function in TCD allogeneic BM transplant recipients, but not in animals that received even modest doses of T cells presumably due to thymic toxicity of the graft-versus-host reaction. Thus, caution must be exercised as IL-7 is developed clinically as an immunorestorative agent for use in the setting of allogeneic BMT. These results suggest that use of IL-7 should be limited to the setting of TCD BMT to obtain the greatest benefit on immune competence with the least toxicity.

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Heterogeneity of thymic epithelial cells in promoting T-lymphocyte differentiation in vivo.

Cited by 51 publications

References 35 publications

Fetal liver pro-B and pre-B lymphocyte clones: expression of lymphoid-specific genes, surface markers, growth requirements, colonization of the bone marrow, and generation of B lymphocytes in vivo and in vitro.

Fetal liver pro-B and pre-B lymphocyte clones: expression of lymphoid-specific genes, surface markers, growth requirements, colonization of the bone marrow, and generation of B lymphocytes in vivo and in vitro.

Interleukin‐7 (IL‐7) in Colorectal Cancer: IL‐7 is Produced by Tissues from Colorectal Cancer and Promotes Preferential Expansion of Tumour Infiltrating Lymphocytes

Interleukin 7 worsens graft-versus-host disease

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