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Journal ArticleDOI

Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages.

TL;DR: It is shown that Id2 is broadly expressed in all cDC subsets with the highest expression in CD103+ and CD8α+ lineages and that Irf‐8 and Batf3 regulate distinct stages in DC differentiation during the development of cDCs.
Abstract: Dendritic cells (DCs) have critical roles in the induction of the adaptive immune response. The transcription factors Id2, Batf3 and Irf-8 are required for many aspects of murine DC differentiation including development of CD8α+ and CD103+ DCs. How they regulate DC subset specification is not completely understood. Using an Id2-GFP reporter system, we show that Id2 is broadly expressed in all cDC subsets with the highest expression in CD103+ and CD8α+ lineages. Notably, CD103+ DCs were the only DC able to constitutively cross-present cell-associated antigens in vitro. Irf-8 deficiency affected loss of development of virtually all conventional DCs (cDCs) while Batf3 deficiency resulted in the development of Sirp-α− DCs that had impaired survival. Exposure to GM-CSF during differentiation induced expression of CD103 in Id2-GFP+ DCs. It did not restore cross-presenting capacity to Batf3−/− or CD103−Sirp-α−DCs in vitro. Thus, Irf-8 and Batf3 regulate distinct stages in DC differentiation during the development of cDCs. Genetic mapping DC subset differentiation using Id2-GFP may have broad implications in understanding the interplay of DC subsets during protective and pathological immune responses.

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Citations
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Journal ArticleDOI
TL;DR: This Opinion article suggests that the mononuclear phagocyte system can be classified primarily by their ontogeny and secondarily by their location, function and phenotype, which permits a more robust classification during both steady-state and inflammatory conditions.
Abstract: The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.

1,404 citations

01 Jan 2010
TL;DR: The data demonstrate a role for CD141+ DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.
Abstract: The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141(+) DC subset. CD141(+) DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-beta, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c(+) DC subset. Polyinosine-polycytidylic acid (poly I:C)-activated CD141(+) DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8(+) cytotoxic T lymphocytes than poly I:C-activated CD1c(+) DCs. Importantly, CD141(+) DCs, but not CD1c(+) DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141(+) DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8 alpha(+) DC subset. The data demonstrate a role for CD141(+) DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

859 citations

Journal ArticleDOI
19 Oct 2012-Immunity
TL;DR: It is demonstrated that GATA-3 is essential for ILC2 fate decisions and similarities between the transcriptional programs controlling ILC and T helper cell fates are revealed.

750 citations


Cites result from "Id2 expression delineates different..."

  • ...CD11c+ DCs were Id2lo (Figure S2B), a finding consistent with a role of Id2 for the development of DC subsets (Hacker et al., 2003; Jackson et al., 2011)....

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  • ...CD11c DCs were Id2 (Figure S2B), a finding consistent with a role of Id2 for the development of DC subsets (Hacker et al., 2003; Jackson et al., 2011)....

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  • ...As previously reported (Jackson et al., 2011), B cells (Figure 3A) and most mononuclear phagocytes (Figure S2B) did not express appreciable amounts of Id2....

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Journal ArticleDOI
TL;DR: The developmental relationships between the various ILC lineages that have been identified to date are reviewed and their functions in protective immunity to infection and their pathological roles in allergic and autoimmune diseases are summarized.
Abstract: Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage that have emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the various ILC lineages that have been identified to date and summarize their functions in protective immunity to infection and their pathological roles in allergic and autoimmune diseases.

657 citations

Journal ArticleDOI
TL;DR: Progress has been made in three critical areas of DC biology: the characterization of lineage-restricted progenitors in the bone marrow, the identification of cytokines and transcription factors required during differentiation, and the development of genetic tools for the visualization and depletion of DCs in vivo.
Abstract: Dendritic cells (DCs) are essential mediators of innate and adaptive immune responses. Study of these critical cells has been complicated by their similarity to other hematopoietic lineages, particularly monocytes and macrophages. Progress has been made in three critical areas of DC biology: the characterization of lineage-restricted progenitors in the bone marrow, the identification of cytokines and transcription factors required during differentiation, and the development of genetic tools for the visualization and depletion of DCs in vivo. Collectively, these advances have clarified the nature of the DC lineage and have provided novel insights into their function during health and disease.

424 citations

References
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Journal ArticleDOI
05 Feb 2010-Science
TL;DR: The current understanding of myeloid lineage development is reviewed and the developmental pathways and cues that drive differentiation are described, which are central to the development of immunologic memory and tolerance in mice.
Abstract: Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.

2,832 citations


"Id2 expression delineates different..." refers background in this paper

  • ...Langerhans cells (LCs) and the dermal DCs are found in skin while migratory tissue-derived CD103þ DCs originate from cutaneous and mucosal tissues such as the lamina propria of respiratory and gastrointestinal tracts (reviewed in Geissmann et al (2010))....

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  • ...DCs can be categorized into a number of different subsets that largely reflect the pattern of expression of cell surface molecules and functional specializations (Geissmann et al, 2010; Steinman and Idoyaga, 2010)....

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Journal ArticleDOI
14 Jan 1994-Cell
TL;DR: Results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.

2,715 citations


Additional excerpts

  • ...1+OT-I CD8+ T cells CFSE Itgae –/–C57BL/6H-2bm-1 0 120 E 98.5 98.0 5.4 0.26 99.7 82.5 17.5 85 15 0 909 84 16 10.6 89.4 12.5 87.5 0 512 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105102 103 104 105102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 76.7 23.3 8.38 91.6 D CFSE CD45RA–Sirp-α+ DCs CD45RAintSirp-α– DCs OT-II CD4+ T cells OT-I CD8+ T cells alone OT-II CD4+ T cells alone CD103– DCs CD103+ DCs OT-I CD8+ T cells CD103 5....

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  • ...Antigen presentation to naive T cells in vitro In all, 2–2.5 104 purified DC subsets were washed and resuspended in 200ml mouse tonicity complete RPMI 1640 medium containing 2 105 OVA-coated irradiated bm1 splenocytes and 1 105 CFSE-labelled OT-I or OT-II T cells....

    [...]

  • ...The presentation of OVA to CFSE-labelled OVA-specific CD4þ T cells (OT-II cells) was used as a control to determine that all populations of DCs could present OVA antigens....

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  • ...CH-2bm-1 (bm1), OT-I (Hogquist et al, 1994), OT-II (Barnden et al, 1998), Batf3 / (Hildner et al, 2008), Irf-8 / (Holtschke et al, 1996) and Itgae / (Schon et al, 2000) mice were used at 6–8 weeks....

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  • ...DCs were purified and then co-cultured with OVA-coated bm-1 splenocytes (which cannot present antigen on H-2Kb) and analysed for their capacity to induce proliferation of CFSE-labelled OVA-specific CD8þ T cells (OT-I cells)....

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Journal ArticleDOI
14 Nov 2008-Science
TL;DR: An important role is suggested for CD8α+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection in Batf3–/– mice.
Abstract: Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α+ dendritic cells, in vivo analysis has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8α+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3–/– mice were defective in cross-presentation, and Batf3–/– mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3–/– mice. These results suggest an important role for CD8α+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.

1,701 citations


"Id2 expression delineates different..." refers background or result in this paper

  • ...…reveals overlapping but non-redundant roles of Irf-8 and Batf3 during CD8aþ DC and CD103þ DC differentiation Id2, Irf-8 and Batf3 are transcription factors implicated in the development of CD103þ and CD8aþ DCs (Schiavoni et al, 2004; Hildner et al, 2008; Ginhoux et al, 2009; Edelson et al, 2010)....

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  • ...This is consistent with earlier observations of reduced Sirp-a DCs following Flt3L culture (Hildner et al, 2008) but notably when we enumerated the Sirp-a splenic precursor cells earlier in culture, they were not significantly impaired....

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  • ...Batf3 is required for the generation of LN-derived DCs of the CD103þ and CD8aþ lineages (Hildner et al, 2008; Edelson et al, 2010)....

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  • ...…Irf-4 (Suzuki et al, 2004) and Irf-8 (Schiavoni et al, 2002, 2004; Tamura et al, 2005), PU.1 (Carotta et al, 2010), Ikaros, Gfi-1 (Rathinam et al, 2005), Batf3 (Hildner et al, 2008) and signal transducer and activator of transcription (Stat)-3 and Stat-5 (Wu and Liu, 2007; Merad and Manz, 2009)....

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  • ...…led to a model in which conventional CD8aþ DCs and CD103þ DCs are thought to be developmentally related and possess similar functional and localization characteristics as both DC subsets are absent in mice lacking Id2, Irf-8 or Batf3 (Hildner et al, 2008; Ginhoux et al, 2009; Edelson et al, 2010)....

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Journal ArticleDOI
TL;DR: Results show that successful generation of MHC class II‐restricted, OVA‐specific αβTCR transgenic mice was dependent upon combining cDNA‐ and genomic DNA‐based constructs for expression of the respective α‐ and β‐chains of the TCR.
Abstract: We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.

1,462 citations


Additional excerpts

  • ...CH-2bm-1 (bm1), OT-I (Hogquist et al, 1994), OT-II (Barnden et al, 1998), Batf3 / (Hildner et al, 2008), Irf-8 / (Holtschke et al, 1996) and Itgae / (Schon et al, 2000) mice were used at 6–8 weeks....

    [...]

  • ...Antigen presentation to naive T cells in vitro In all, 2–2.5 104 purified DC subsets were washed and resuspended in 200ml mouse tonicity complete RPMI 1640 medium containing 2 105 OVA-coated irradiated bm1 splenocytes and 1 105 CFSE-labelled OT-I or OT-II T cells....

    [...]

  • ...The presentation of OVA to CFSE-labelled OVA-specific CD4þ T cells (OT-II cells) was used as a control to determine that all populations of DCs could present OVA antigens....

    [...]

  • ...1+OT-I CD8+ T cells CFSE Itgae –/–C57BL/6H-2bm-1 0 120 E 98.5 98.0 5.4 0.26 99.7 82.5 17.5 85 15 0 909 84 16 10.6 89.4 12.5 87.5 0 512 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105102 103 104 105102 103 104 105 102 103 104 105 102 103 104 105 102 103 104 105 76.7 23.3 8.38 91.6 D CFSE CD45RA–Sirp-α+ DCs CD45RAintSirp-α– DCs OT-II CD4+ T cells OT-I CD8+ T cells alone OT-II CD4+ T cells alone CD103– DCs CD103+ DCs OT-I CD8+ T cells CD103 5....

    [...]

Journal ArticleDOI
TL;DR: The three presumably novel Ags serve as specific markers for the respective subpopulations of blood dendritic cells in fresh blood and will be of great value for their further analysis and to evaluate their therapeutic potential.
Abstract: We have generated a panel of mAbs that identify three presumably novel human dendritic cell Ags: BDCA-2, BDCA-3, and BDCA-4. In blood, BDCA-2 and BDCA-4 are expressed on CD11c− CD123bright plasmacytoid dendritic cells, whereas BDCA-3 is expressed on small population of CD11c+ CD123− dendritic cells. All three Ags are not detectable on a third blood dendritic cell population, which is CD1c+ CD11cbright CD123dim, or on any other cells in blood. BDCA-4 is also expressed on monocyte-derived and CD34+ cell-derived dendritic cells. Expression of all three Ags dramatically changes once blood dendritic cells undergo in vitro maturation. BDCA-2 is completely down-regulated on plasmacytoid CD11c− CD123bright dendritic cells, expression of BDCA-3 is up-regulated on both plasmacytoid CD11c− CD123bright dendritic cells and CD1c+ CD11cbright CD123dim dendritic cells, and expression of BDCA-4 is up-regulated on CD1c+ CD11cbright CD123dim dendritic cells. BDCA-2 is rapidly internalized at 37°C after mAb labeling. The three presumably novel Ags serve as specific markers for the respective subpopulations of blood dendritic cells in fresh blood and will be of great value for their further analysis and to evaluate their therapeutic potential.

1,356 citations


"Id2 expression delineates different..." refers background in this paper

  • ...DC subsets in the human blood can be distinguished by their expression of the surface molecules BDCA-1 (CD1c), BDCA-2 (CD303) and BDCA-3 (CD141) (Dzionek et al, 2000)....

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  • ...XCR1, a chemokine receptor expressed on murine splenic CD8aþ DCs (Dorner et al, 2009) together with CD103þ DCs, appears also to define the CD11cþCD141þ human homologues of mouse CD8aþ DCs (Bachem et al, 2010; Crozat et al, 2010; Jongbloed et al, 2010; Poulin et al, 2010)....

    [...]

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