Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus

Stromal fibroblasts are important for normal breast homeostasis and regulation of epithelial growth; however, this regulatory function is altered during carcinogenesis. To study the role of fibroblasts in the development of breast cancer, fibroblasts derived from normal breast (NAFs) were incorporated into the MCF10AT xenograft model of progressive proliferative breast disease. The persistence of human NAFs in xenografts was established by intracellular labeling and tyramide-coupled fluorescent in situ hybridization. Overall, the number of MCF10AT epithelial structures was decreased, and the rate of epithelial cell apoptosis was increased in xenografts containing NAFs. However, these changes were primarily in low-grade epithelial structures, corresponding to normal or mildly hyperplastic ductal epithelium. The level and rate of apoptosis of high-grade epithelial structures, corresponding to in situ and invasive carcinoma, were not consistently altered by NAFs. In addition, there was variability in the growth-inhibitory capacity of NAFs derived from different individuals. NAFs induced changes in the morphology of high-grade MCF10AT structures and in xenograft stroma, including the composition of extracellular matrix, and increased angiogenesis and lymphocytic infiltration. These findings imply that NAFs can inhibit the growth of normal and hyperplastic epithelium but are less able to regulate the more transformed epithelial cells that arise during carcinogenesis. (Am J Pathol 2007, 170

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“…28,29 As expected, infiltration by CD3-positive lymphocytes was overall lower than B220-positive, B-cell infiltration.…”

Section: Inflammatory Infiltratementioning

confidence: 81%

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Sadlonova

Mukherjee

Bowe

et al. 2007

The American Journal of Pathology

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“…The Ando-2 melanoma cell line presents surface expression of one HLA class I haplotype but, after growth in nude mice, the derived Ando-Nude melanoma cell lines presented total absence of HLA class I molecule surface expression. These AndoNude cells might have appeared by an immunoselection of rare HLA-negative cells, in which extrathymic T lymphocytes present in nude mice might have been implicated, 20,21 although it has been shown that these extrathymic T lymphocytes cannot functionally substitute classic thymic T cells. 22 It is also possible that NK cells present in nude mice might xenogenically recognise Ando-2 melanoma cells and produce immunoselection of AndoNude melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response

Paco

García-Lora

Casares

et al. 2007

Intl Journal of Cancer

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Loss of HLA class I expression on tumor cells is a frequent event as an immune escape mechanism. Seven different altered HLA phenotypes have been defined in tumors. Various molecular mechanisms have been described as responsible for HLA class I loss. HLA class I expression alterations occur successively and unpredictably during tumor progression in vivo and immunoselection has been implicated in this process. We present an experimental xenograft model in which melanoma cell line Ando-2 injected into athymic nude mice lost total surface HLA class I expression and exhibited HLA class II cell surface expression. A strong down-regulation of HLA class I expression and de novo HLA class II expression were also found when Ando-2 melanoma cells were injected into SCID-Beige mice. These phenomena were reproducible and were only observed in local growth in nude or SCID-Beige mice and not in vitro after multiple passages. HLA class I surface expression was recovered after IFN-c treatment, indicating regulatory defects. The mechanism implicated in loss of HLA class I molecule expression were a down-regulation of different components of antigen processing machinery and HLA class I heavy chains. These data suggest that HLA class I alterations can also occur in absence of autologous adaptive immune response. This is a good experimental in vivo model to study the relationship between tumor progression and HLA class I alterations. ' 2007 Wiley-Liss, Inc.

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“…These pre-T cells arise before the generation of early thymic progenitors (ETPs) (L. Gautreau and S. Ezine, unpublished observations) (16) and accumulate in the spleen after thymectomy (15), representing the first stage of an early T cell pathway. Splenic and medullary progenitors generate T cells upon adoptive transfer, but additional NK cells develop from the latter population (12). We demonstrated that these splenic pre-T cells depend on Notch signaling for their generation (17).…”

Section: Flt3mentioning

confidence: 91%

“…Meanwhile, progenitors with restricted T-lineage potential have been described in the gut (10,11), the BM (12), and the spleen (13)(14)(15). In fact, Lin 2 Thy1.2 + CD25 + IL7Ra + T cell precursors (pre-T cells) are naturally present in murine spleen (14,15) and are also found in the spleen after BM transplantation (13).…”

Section: Flt3mentioning

confidence: 99%

Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment

Zepponi

Lopez

Martínez-Cingolani

et al. 2015

The Journal of Immunology

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Extrathymic T cell precursors can be detected in many tissues and represent an immediately competent population for rapid T cell reconstitution in the event of immunodeficiencies. Blood T cell progenitors have been detected, but their source in the bone marrow (BM) remains unclear. Prospective purification of BM-resident and circulating progenitors, together with RT-PCR single-cell analysis, was used to evaluate and compare multipotent progenitors (MPPs) and common lymphoid progenitors (CLPs). Molecular analysis of circulating progenitors in comparison with BM-resident progenitors revealed that CCR9+ progenitors are more abundant in the blood than CCR7+ progenitors. Second, although Flt3− CLPs are less common in the BM, they are abundant in the blood and have reduced Cd25+-expressing cells and downregulated c-Kit and IL-7Rα intensities. Third, in contrast, stage 3 MPP (MPP3) cells, the unique circulating MPP subset, have upregulated Il7r, Gata3, and Notch1 in comparison with BM-resident counterparts. Evaluation of the populations’ respective abilities to generate splenic T cell precursors (Lin−Thy1.2+CD25+IL7Rα+) after grafting recipient nude mice revealed that MPP3 cells were the most effective subset (relative to CLPs). Although several lymphoid genes are expressed by MPP3 cells and Flt3− CLPs, the latter only give rise to B cells in the spleen, and Notch1 expression level is not modulated in the blood, as for MPP3 cells. We conclude that CLPs have reached the point where they cannot be a Notch1 target, a limiting condition on the path to T cell engagement.

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Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus

Cited by 26 publications

References 34 publications

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Human Breast Fibroblasts Inhibit Growth of the MCF10AT Xenograft Model of Proliferative Breast Disease

Total loss of HLA class I expression on a melanoma cell line after growth in nude mice in absence of autologous antitumor immune response

Lymphoid Gene Upregulation on Circulating Progenitors Participates in Their T-Lineage Commitment

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