Deciphering the transcriptional network of the DC
lineage

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Abstract

Although, much progress has been made in our understanding of DC ontogeny and function, the transcriptional regulation of DC lineage commitment and functional specialization in vivo is poorly understood. We performed a comprehensive comparative analysis of CD8+, CD103+, CD11b+, and plasmacytoid DC subsets and the recently identified Macrophage DC precursors and Common DC precursors across the entire immune system. Here we characterize candidate transcriptional activators involved in myeloid progenitor commitment to the DC lineage and predicted regulators of DC functional diversity in tissues. We identify a molecular signature that distinguishes tissue DC from macrophages. We also identify a transcriptional program expressed specifically during steady-state tissue DC migration to the draining lymph nodes that may control tolerance to self-tissue antigens.

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Most cited references 45

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Taking dendritic cells into medicine.

Ralph M. Steinman, Jacques Banchereau (2007)

Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.

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Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells

Annabell Bachem, Steffen Güttler, Evelyn Hartung … (2010)

In recent years, human dendritic cells (DCs) could be subdivided into CD304+ plasmacytoid DCs (pDCs) and conventional DCs (cDCs), the latter encompassing the CD1c+, CD16+, and CD141+ DC subsets. To date, the low frequency of these DCs in human blood has essentially prevented functional studies defining their specific contribution to antigen presentation. We have established a protocol for an effective isolation of pDC and cDC subsets to high purity. Using this approach, we show that CD141+ DCs are the only cells in human blood that express the chemokine receptor XCR1 and respond to the specific ligand XCL1 by Ca2+ mobilization and potent chemotaxis. More importantly, we demonstrate that CD141+ DCs excel in cross-presentation of soluble or cell-associated antigen to CD8+ T cells when directly compared with CD1c+ DCs, CD16+ DCs, and pDCs from the same donors. Both in their functional XCR1 expression and their effective processing and presentation of exogenous antigen in the context of major histocompatibility complex class I, human CD141+ DCs correspond to mouse CD8+ DCs, a subset known for superior antigen cross-presentation in vivo. These data define CD141+ DCs as professional antigen cross-presenting DCs in the human.

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CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions.

Lars Ohl, Mariette Mohaupt, Niklas Czeloth … (2004)

The CC chemokine receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this receptor is dispensable for the mobilization of Langerhans cells from the epidermis to the dermis. Moreover, a distinct population of CD11c(+)MHCII(high) DC showing low expression of the costimulatory molecules CD40, CD80, and CD86 in wild-type animals was virtually absent in skin-draining lymph nodes of CCR7-deficient mice under steady-state conditions. We provide evidence that these cells represent a semimature population of DC that is capable of initiating T cell proliferation under conditions known to induce tolerance. Thus, our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.

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Author and article information

Journal

Journal ID (nlm-journal-id): 100941354

Journal ID (pubmed-jr-id): 21750

Journal ID (nlm-ta): Nat Immunol

Journal ID (iso-abbrev): Nat. Immunol.

Title: Nature immunology

ISSN (Print): 1529-2908

ISSN (Electronic): 1529-2916

Publication date Nihms-submitted: 23 January 2014

Publication date (Electronic): 15 July 2012

Publication date (Print): September 2012

Publication date PMC-release: 14 April 2014

Volume: 13

Issue: 9

Pages: 888-899

Affiliations

[1 ]Immunology Institute, Mount Sinai School of Medicine New York, NY, USA

[2 ]Department of Oncological sciences, Mount Sinai School of Medicine New York, NY, USA

[3 ]Institute for Genomics and Multiscale Biology and Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine New York, NY, USA

[4 ]Broad Institute, Cambridge, MA 02142, USA

[5 ]Department of Regenerative Biology, Mount Sinai School of Medicine New York, NY, USA

[6 ]Department of Pathology & Immunology, Washington University in St. Louis, St. Louis, MO, USA

[7 ]Computer Science department, Stanford University, Stanford, CA

[9 ]Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA, USA

[10 ]Albert Einstein College of Medicine, Bronx, NY

Author notes

Corresponding author: Miriam Merad, M.D., Ph.D., 1425 Madison Avenue, Box 1496, Tel: 212 659 8276, Miriam.merad@ 123456mssm.edu

[8]

Present address: Department of Computer Science, UNC, Chapel Hill, NC

Article

Manuscript ID: NIHMS384129

DOI: 10.1038/ni.2370

PMC ID: 3985403

PubMed ID: 22797772

SO-VID: 6acdfc63-ae4a-4abd-8882-78fbdc4bc676

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Deciphering the transcriptional network of the DC lineage

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HLA-G and immune tolerance in pregnancy

Most cited references 45

Taking dendritic cells into medicine.

Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells

CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions.

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