Liver-Derived DEC205+B220+CD19− Dendritic Cells Regulate T Cell Responses

Lü, Lina; Bonham, Clark A.; Liang, Xiaoyan; Chen, Z.; Li, W.; Wang, L.; Watkins, Simon C.; Nalesnik, Michael A.; Schlissel, Mark S.; Demestris, A. J.; Fung, John J.; Shen, Qian

doi:10.4049/jimmunol.166.12.7042

Cited by 85 publications

(95 citation statements)

References 65 publications

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“…Importantly, some of these presumptive APCs, which acquire regulatory properties in the immunosuppressive (immunologically privileged) environment of the eye (46), accumulate as CD11c ϩ DCs in the thymus of the adoptive recipients (5) (our unpublished observations). It is possible that, under steady state conditions, these regulatory DCs are represented by the minor population of CD8␣ Ϫ/low F4/80 low thymic DCs (29) or by B220 ϩ plasmacytoid DCs, which have been reported to have tolerogenic potential (1,47). Chiffoleau et al (6) have provided yet another example of the ability of presumptive DCs to migrate to the thymus under tolerogenic conditions.…”

Section: Discussionmentioning

confidence: 99%

Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions

Donskoy

Goldschneider

2003

The Journal of Immunology

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Although a variety of lymphoid and myeloid precursors can generate thymic dendritic cells (DCs) under defined experimental conditions, the developmental origin(s) of DCs in the steady state thymus is unknown. Having previously used selective combinations of normal, parabiotic, and radioablated mice to demonstrate that blood-borne prothymocytes are imported in a gated and competitive manner, we used a similar approach in this study to investigate the importation of the hematogenous precursors of thymic DCs. The results indicate that two developmentally distinct populations of DC precursors normally enter the adult mouse thymus. The first population is indistinguishable from prothymocytes according to the following criteria: 1) inefficient (<20%) exchange between parabiotic partners; 2) gated importation by the thymus; 3) competitive antagonism for intrathymic niches; 4) temporally linked generation of thymocytes and CD8αhigh DCs; and 5) absence from prothymocyte-poor blood samples. The second population differs diametrically from prothymocytes in each of these properties, and appears to enter the thymus in at least a partially differentiated state. The resulting population of DCs has a CD8α−/low phenotype, and constitutes ∼50% of total thymic DCs. The presence of two discrete populations of DCs in the steady state thymus implies functional heterogeneity consistent with evidence implicating lymphoid DCs in the negative selection of effector thymocytes and myeloid DCs in the positive selection of regulatory thymocytes.

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Section: Discussionmentioning

confidence: 99%

Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions

Donskoy

Goldschneider

2003

The Journal of Immunology

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“…6,7,11,[24][25][26] We have shown that transient (Ͻ1 week) overexpression of GM-CSF results in up to a 400-fold increase in hepatic CD11c ϩ DEC205 Ϫ DCs to more than 100 million cells (Fig. 3C).…”

Section: Discussionmentioning

confidence: 99%

Gm–Csf Expands Dendritic Cells and Their Progenitors in Mouse Liver

Pillarisetty

2003

Hepatology

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Dendritic cells (DCs) are rare but ubiquitous antigen-presenting cells situated in lymphoid and nonlymphoid organs throughout the body. The study of DCs located in the liver has been restricted by their relative scarcity and the difficulty of their isolation. Because granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical growth factor for DCs in vitro, we postulated that it would expand hepatic DCs in vivo. We found that adenoviralmediated GM-CSF overexpression in normal mice increased the number of liver DCs 400-fold to more than 100 million cells. GM-CSF-recruited DCs were CD11c ؉ DEC205 ؊ and had high expression of major histocompatibility complex (MHC) class II, CD54, and CD80 but low CD40 and CD86 staining. Further maturation occurred after overnight culture. In addition to CD11c ؉ DEC205 ؊ DCs, a population of CD11c ؊ DEC205 low/؊ cells resembling DC progenitors described previously in normal mice was expanded as serum GM-CSF levels increased. GM-CSF-recruited CD11c D endritic cells (DCs) are rare, heterogeneous leukocytes that are primarily responsible for the capture of antigens in the periphery and subsequent presentation to immune effector cells. 1-3 Although there is a large and rapidly expanding body of data regarding the phenotype and function of murine bone marrowderived DCs and splenic DCs, our understanding of hepatic DCs is rudimentary. [4][5][6] This is due to the scarcity of hepatic DCs and the difficulty of isolating them from normal mice. Most of our knowledge emanates from using granulocyte-macrophage colony-stimulating factor (GM-CSF) to propagate liver DCs in vitro from DC progenitors contained within hepatic nonparenchymal cells (NPCs). 7,8 This approach is analogous to the method commonly used to produce DCs from bone marrow cells. 4 Hepatic DC progenitors have low expression of major histocompatibility complex (MHC) class II and the DC-restricted markers DEC205, CD11c, and 33D1 and produce only low levels of allostimulation in a mixed leukocyte reaction. 7 However, they can differentiate (i.e., gain CD11c and MHC class II expression) into immature DCs in vitro in the presence of GM-CSF. After additional culture on type-1 collagen, the immature liver DCs then become mature with increased surface costimulatory molecule expression and T-cell stimulatory capacity. 7 More recently, the phenotype of freshly isolated CD11c ϩ liver DCs has been described. Consistent with studies of hepatic DCs propagated from DC progenitors in vitro, it was shown that freshly isolated liver DCs were immature, with low MHC class II and costimulatory molecule (CD40, CD80, and CD86) expression. 9 The ability of freshly isolated liver DCs to stimulate T cells has not been well defined.

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“…The remaining CD3 − fraction contained a significant number of cells that were not stained with lineage-specific mAbs for CD3, CD19, or CD56. Several experimental studies have reported that the liver contains heterogenous leukocyte subsets: immature dendritic cells [21,22], immature B cells [23], and NK T cells [24]. Although some authors have attributed tolerogenic properties to these cells, further studies will be needed to determine if such "lineage negative" have a special role in tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

Four-color flow cytometric analysis of peripheral blood donor cell chimerism

et al. 2003

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Passenger leukocytes have been demonstrated to play significant roles in initiating and also regulating immune reactions after organ transplantation. Reliable techniques to detect donor leukocytes in recipients after organ transplantation are essential to analyze the role, function, and behavior of these leukocytes. In this report we describe a simple, reliable method to detect donor cells with low frequencies using peripheral blood samples. Detection of small numbers of major histocompatibility complex (MHC) mismatched cells was first studied using four-color flow cytometry in artificially created cell mixtures. By selecting the CD45 + population and simultaneous staining with several leukocyte lineage markers (CD3, CD4, CD8, CD56, and CD19), MHC-mismatched leukocytes were consistently detected in cell suspensions prepared from directly stained whole blood samples with a threshold sensitivity as low as 0.1%-0.2%. When the fresh peripheral blood mononuclear cells were separated by conventional Ficoll gradient purification, similar, but slightly lower levels of donor cells were detected. Blood samples obtained 1-5 months after liver, kidney, and intestine transplants revealed that the kind of organ allograft influenced levels and lineage pattern of the circulating donor cells. This procedure provided a simple and reliable method in determining early chimerism in transplant recipients. However, the detection of MHC-mismatched leukocytes of all lineages was much lower when frozen peripheral blood mononuclear cells were used.

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Liver-Derived DEC205+B220+CD19− Dendritic Cells Regulate T Cell Responses

Cited by 85 publications

References 65 publications

Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions

Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions

Gm–Csf Expands Dendritic Cells and Their Progenitors in Mouse Liver

Four-color flow cytometric analysis of peripheral blood donor cell chimerism

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