DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues

Poulin, Lionel Franz; Reyal, Yasmin; Uronen-Hansson, Heli; Schraml, Barbara U.; Sancho, David; Murphy, Kenneth M.; Håkansson, Ulf; Moita, Luís F.; Agace, William W.; Bonnet, Dominique; Sousa, Caetano Reis e

doi:10.1182/blood-2012-01-406967

Cited by 216 publications

(211 citation statements)

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“…The strong coexpression of CADM1, CD162, CD205, and XCR1, in combination with quantitative analysis of genes specific for the different myeloid and DC subsets, confirmed the homology among simian, human, and murine XCR1 + mDC. Particularly, in the three species, these cells expressed selectively high levels of the transcription factor Batf3, which specifically drives the development of XCR1 + mouse (CD8a + ) and human (CD141 + ) mDC at steady state (1,62). Macaque XCR1 + mDC strongly expressed the TLR3 gene and strongly responded to the TLR3 ligand poly(I:C) by producing TNF-a and upregulating CD40, whereas all of the other APCs responded weakly or not.…”

Section: Discussionmentioning

confidence: 99%

TLR3–Responsive, XCR1+, CD141(BDCA-3)+/CD8α+-Equivalent Dendritic Cells Uncovered in Healthy and Simian Immunodeficiency Virus–Infected Rhesus Macaques

Dutertre¹,

Jourdain²,

Rancez³

et al. 2014

The Journal of Immunology

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In mice, CD8α+ myeloid dendritic cells (mDC) optimally cross-present Ags to CD8+ T cells and respond strongly to TLR3 ligands. Although equivalent DC have been identified by comparative genomic analysis and functional studies in humans as XCR1+CD141 (BDCA-3)+Clec9A+cell adhesion molecule 1+ mDC, and in sheep as CD26+ mDC, these cells remained elusive in nonhuman primates. To remedy this situation, we delineated precisely DC and monocyte populations by 12-color flow cytometry and transcriptomic analyses in healthy rhesus macaques. We identified a new mDC population, with strong phenotypic and transcriptional homology to human CD141+ and murine CD8α+ mDC, including XCR1 membrane expression as a conserved specific marker. In contrast, high CD11c expression was not characteristic of mDC in macaques, but of CD16+ monocytes. Like their human and murine homologs, simian XCR1+ mDC had much stronger responses to TLR3 stimulation than other myeloid cells. The importance of this new mDC population was tested in SIVmac251 infection, the most relevant animal model for pathogenic HIV-1 infection and vaccination. This population increased sharply and transiently during acute infection, but was reduced in blood and spleen during advanced disease. The identification of XCR1+ mDC in rhesus macaques opens new avenues for future preclinical vaccinal studies and highlights XCR1 as a prime candidate for targeted vaccine delivery.

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Section: Discussionmentioning

confidence: 99%

TLR3–Responsive, XCR1+, CD141(BDCA-3)+/CD8α+-Equivalent Dendritic Cells Uncovered in Healthy and Simian Immunodeficiency Virus–Infected Rhesus Macaques

Dutertre¹,

Jourdain²,

Rancez³

et al. 2014

The Journal of Immunology

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“…This might be attributable to the persistence of CD103 ϩ DCs and precursors of CD8␣ ϩ DCs in the absence of Batf3. 6,7,44 In unmanipulated Batf3 Ϫ/Ϫ mice, CD8␣ ϩ DCs that express the marker Clec9A (also known as DNGRI 45,46 ) are detectable and splenic precursors to CD8␣ ϩ (pre-CD8␣ ϩ , CD8 Ϫ CD24 ϩ MHCII ϩ ) DCs are expanded 3-fold 44 implying that Batf3 either regulates the development of this subset 46 or that Clec9A is a direct target of Batf3. An alternative proposal is that Batf3 may have specific effects on the cross-presenting pathway for cell-associated antigens accounting for the lack of cross-presentation observed in in vitro cultures.…”

Section: Discussionmentioning

confidence: 99%

CD8α+ DCs can be induced in the absence of transcription factors Id2, Nfil3, and Batf3

Seillet

Jackson

Markey

et al. 2013

Blood

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Key Points• Transcription factors Batf3, Id2, and Nfil3 are not essential for induced CD8␣ ϩ DC generation.• Induced CD8␣ ؉ DCs can crosspresent cellular antigens. Antiviral immunity and cross-presentation is mediated constitutively through CD8␣؉ and CD103 ؉ DCs. Development of these DC subsets is thought to require the transcription factors Irf8, Id2, Nfil3, and Batf3, although how this network is regulated is poorly defined. We addressed the nature of the differentiation blocks observed in the absence of these factors and found that although all 4 factors are required for CD103 ؉ DC development, only Irf8 is essential for CD8␣ ؉ DCs. CD8␣ ؉ DCs emerged in the absence of Id2, Nfil3 and Batf3 in short-term bone marrow reconstitution. These "induced" CD8␣ ؉ DCs exhibit several hallmarks of classic CD8␣ ؉ DCs including the expression of CD24, Tlr3, Xcr1, Clec9A, and the capacity to cross-present soluble, cell-associated antigens and viral antigens even in the absence of Batf3. Collectively, these results uncover a previously undescribed pathway by which CD8␣ ؉ DCs emerge independent of Id2, Nfil3, and Batf3, but dependent on Irf8. (Blood. 2013;121(9):1574-1583) Introduction CD103 ϩ and CD8␣ ϩ dendritic cells (DCs) are important for cross-presentation of antigens and for the induction of effector CD8 ϩ T-cell responses against pathogens. Differentiation of these 2 subsets is regulated by a common set of transcription factors including interferon regulatory factor 8 (Irf8), nuclear factor interleukin 3-regulated (Nfil3 or E4BP4) and Id2 (inhibitor of DNA binding 2). [1][2][3][4] Both populations also express the transcription factor Batf3 (basic leucine zipper transcriptional factor ATF-like 3, also known as Jun dimerization protein p21SNFT) 2,5 but display differential dependence on Batf3 for differentiation. 6,7 In initial studies, loss of Batf3 was thought to be critical for the development of CD8␣ ϩ DCs which provided an elegant explanation for the inability of Batf3 Ϫ/Ϫ mice (generated on a B6.129 background) to cross-present cell-associated or viral antigens. 5 Subsequently, these mice were discovered to also lack CD103 ϩ DCs. 2 This allowed confirmation of the hypothesis that CD103 ϩ DCs from the lung were important for capture and transport of antigen to the draining lymph node (LN) where an immune response is initiated after inflammation or infection. [8][9][10] Despite this, it has been observed that at steady-state in mice of a C57BL/6 genetic background, a population of DCs that express low levels of CD8␣ persist in spleen and LNs, and CD8␣ ϩ DC precursors can be identified in vitro in response to Flt3L stimulation. 6,7 Furthermore, CD103 expression could be induced in vitro on DCs after addition of GM-CSF even in the absence of Batf3. 6,7 Collectively, these findings raise major questions concerning the exact role of Batf3 Ϫ/Ϫ in DC differentiation and function.We now report that Batf3 intrinsically controls the development of CD103 ϩ Epcam ϩ DCs and the ability to cross-present cellassociated, but not ...

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“…34 We speculated that this also holds true for Clec9A, a more specific marker of the CD8a-like cDC lineage, recently shown to be already expressed by DC precursors. 35,36 Interestingly, pre-DCs start to express Clec9A on day 6 and Clec9A expression peaks on day 9, with about 30% of pre-DCs being Clec9A 1 in both FL-DC and iCD103-DC cultures ( Figure 4B-C). Thus, by comparing FL-DC and iCD103-DC cultures, GM-CSF has little effect on Clec9A expression ( Figure 4B) and Clec9A 1 pre-DC numbers ( Figure 4C).…”

Section: Gm-csf Supernatant Selectively Promotes the Differentiation mentioning

confidence: 99%

Selective and efficient generation of functional Batf3-dependent CD103+ dendritic cells from mouse bone marrow

Mayer

Ghorbani

Nandan

et al. 2014

Blood

168

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DNGR-1 is a specific and universal marker of mouse and human Batf3-dependent dendritic cells in lymphoid and nonlymphoid tissues

Cited by 216 publications

References 50 publications

TLR3–Responsive, XCR1+, CD141(BDCA-3)+/CD8α+-Equivalent Dendritic Cells Uncovered in Healthy and Simian Immunodeficiency Virus–Infected Rhesus Macaques

TLR3–Responsive, XCR1+, CD141(BDCA-3)+/CD8α+-Equivalent Dendritic Cells Uncovered in Healthy and Simian Immunodeficiency Virus–Infected Rhesus Macaques

CD8α+ DCs can be induced in the absence of transcription factors Id2, Nfil3, and Batf3

Selective and efficient generation of functional Batf3-dependent CD103+ dendritic cells from mouse bone marrow

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