Review
Human mononuclear phagocyte system reunited

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Abstract

The human mononuclear phagocyte network comprises dendritic cells (DCs), monocytes and macrophages with a range of immune functions including antigen presentation linking innate and adaptive immunity. A number of DC, monocyte and macrophage subsets have been described in lymphoid and non-lymphoid tissues of mouse and human, with increased understanding of their distinct functional properties and genetic and cellular pathways of development. More recently, through comparative biology studies, a unified nomenclature of mononuclear phagocytes has begun to emerge with the identification of homologous subsets in several species. In this review, we discuss the current classification of human mononuclear phagocytes and the parallel organization of this network in the mouse. We also review the genetic control and developmental pathway of human mononuclear phagocytes and the immunological functions of the distinct subsets in health and inflammation.

Introduction

Dendritic cells (DCs), monocytes and macrophages are a heterogeneous population of mononuclear cells that are specialized in antigen processing and presentation to initiate and regulate immune responses (reviewed in [1], [2], [3]). In addition to their afferent sentinel functions, DCs and macrophages are also coordinators and effectors of homeostasis and inflammation in peripheral tissues [4], [5], [6]. There has been a paradigm shift in our understanding of mononuclear phagocytes beyond the traditional view of DCs and macrophages as functional variations of monocytes. Significant progress has been made in understanding human and mouse mononuclear phagocyte biology in tandem, including a number of important recent conceptual advances concerning their ontogeny and development (reviewed in [7], [8], [9], [10], [11]). An exceptionally fruitful strategy to integrate these findings has been comparative analysis of mouse and human, which has identified homologous subsets and facilitated a unified classification of mononuclear phagocytes across species [12], [13], [14], [15], [16], [17], [18], [19], [20].

While harnessing DCs and macrophages for therapeutic purposes has major implications for infectious disease, vaccine science, transplantation, tolerance induction, inflammation and cancer immunotherapy, the use of monocyte-derived DCs in therapy has so far been underwhelming (reviewed in [21], [22]). A thorough understanding of the origin and immune function of human mononuclear phagocytes in vivo may direct our attentions to more effective therapeutic strategies.

Section snippets

The mononuclear phagocyte family

Mononuclear phagocytes, in contrast to polymorphonuclear granulocytes (originally known as microphages), are leukocytes with specialized antigen processing and presentation function. They are found in almost all tissue compartments, including peripheral blood and are often referred to as antigen presenting cells (APCs). The ‘mononuclear phagocyte system’ was proposed in the late 1960s by van Furth to include circulating monocytes and tissue macrophages [23], the latter assumed to be

Non-lymphoid tissue

Although epidermal Langerhans cells (LCs) were first described in 1868[54], their identity as a member of the mononuclear phagocyte system was not appreciated until 1977, when they were found to express MHC Class II and complement receptors [55], [56], [57]. A notable property of some mononuclear phagocytes and lymphocytes from the skin is their ability to migrate spontaneously from skin explants cultured ex vivo [58], [59], [60], [61]. Spontaneous migration which occurs over 1–3 days from

Murine homologs of human mononuclear phagocytes

Recent comparative studies have provided a framework to unify the classification of mononuclear phagocytes between humans, mice and other species. Homologous subsets were identified by transcriptome profile, function and phenotype analysis. Human CD141+ DCs are homologous to mouse CD8/CD103+ DCs. Several markers including XCR1 [90], NECL2/CADM1 [91], TLR3 [92] and CLEC9A [69], [93], [94] are conserved across species. Ongoing research is focused on testing these antigens as universal markers for

CD141+ myeloid DCs (cDC1)

CD141+ DCs secrete TNFα, CXCL10 and IFNλ but little IL-12p70, in contrast to monocyte-derived DCs [17], [146], [147]. The homology of CD141+ DCs to murine CD8+/CD103+ DCs suggested potent cross-presentation function for this subset. CD141+ DCs have been shown to be superior at cross-presenting necrotic cell-derived and soluble antigen via CLEC9A [13], [94] and upon TLR3 stimulation with poly I:C [13], [15], [16], [17] in vitro. However, in vitro cross-presentation function is not restricted to

Conclusions

There has been tremendous progress in our understanding of the human mononuclear phagocyte network and function in recent years. The application of unbiased transcriptome profiling, comprehensive analysis of tissue, blood and bone marrow, and the iterative inter-species comparisons between human and mouse has provided the means and resolution to interrogate the complexity and heterogeneity of mononuclear phagocytes in human. However, there are still known unknowns and unknown unknowns, which

Acknowledgements

We would like to acknowledge funding from the Wellcome Trust (WT088555 to M.H. and WT101155/Z/13/Z to V.B.), British Skin Foundation, Leukaemia Research, the Histiocytosis Association and Bright Red.

References (195)

  • N.V. Serbina et al.

    TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection

    Immunity

    (2003)
  • C. Cheong et al.

    Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas

    Cell

    (2010)
  • B. Leon et al.

    Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania

    Immunity

    (2007)
  • A. Wollenberg et al.

    Expression and function of the mannose receptor CD206 on epidermal dendritic cells in inflammatory skin diseases

    J Invest Dermatol

    (2002)
  • E. Segura et al.

    Human inflammatory dendritic cells induce th17 cell differentiation

    Immunity

    (2013)
  • X.N. Wang et al.

    A three-dimensional atlas of human dermal leukocytes, lymphatics, and blood vessels

    J Invest Dermatol

    (2014)
  • C. Huysamen et al.

    CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes

    J Biol Chem

    (2008)
  • L.F. Poulin et al.

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

    Blood

    (2012)
  • E. Klechevsky et al.

    Understanding human myeloid dendritic cell subsets for the rational design of novel vaccines

    Hum Immunol

    (2009)
  • K.L. Summers et al.

    Phenotypic characterization of five dendritic cell subsets in human tonsils

    Am J Pathol

    (2001)
  • K. Takahashi et al.

    Heterogeneity of dendritic cells in human superficial lymph node: in vitro maturation of immature dendritic cells into mature or activated interdigitating reticulum cells

    Am J Pathol

    (1998)
  • R. van de Ven et al.

    Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation

    Blood

    (2011)
  • K.P. MacDonald et al.

    Characterization of human blood dendritic cell subsets

    Blood

    (2002)
  • M. O’Keeffe et al.

    Dendritic cell precursor populations of mouse blood: identification of the murine homologues of human blood plasmacytoid pre-DC2 and CD11c+ DC1 precursors

    Blood

    (2003)
  • L. Ziegler-Heitbrock et al.

    Nomenclature of monocytes and dendritic cells in blood

    Blood

    (2010)
  • K. Schakel et al.

    6-Sulfo LacNAc, a novel carbohydrate modification of PSGL-1, defines an inflammatory type of human dendritic cells

    Immunity

    (2002)
  • B.G. Dorner et al.

    Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic cells determines cooperation with CD8+ T cells

    Immunity

    (2009)
  • L. Galibert et al.

    Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule

    J Biol Chem

    (2005)
  • I. Caminschi et al.

    The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement

    Blood

    (2008)
  • M.A. Ingersoll et al.

    Comparison of gene expression profiles between human and mouse monocyte subsets

    Blood

    (2010)
  • J. Cros et al.

    Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors

    Immunity

    (2010)
  • K.L. Wong et al.

    Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets

    Blood

    (2011)
  • X.M. Dai et al.

    Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects

    Blood

    (2002)
  • J. Banchereau et al.

    Dendritic cells and the control of immunity

    Nature

    (1998)
  • R.M. Steinman

    Lasker Basic Medical Research Award, Dendritic cells: versatile controllers of the immune system

    Nat Med

    (2007)
  • M. Merad et al.

    The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting

    Annu Rev Immunol

    (2013)
  • A. Abtin et al.

    Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection

    Nat Immunol

    (2014)
  • Y. Natsuaki et al.

    Perivascular leukocyte clusters are essential for efficient activation of effector T cells in the skin

    Nat Immunol

    (2014)
  • R.L. Lakey et al.

    A novel paradigm for dendritic cells as effectors of cartilage destruction

    Rheumatology (Oxford)

    (2009)
  • K. Liu et al.

    Origin and development of dendritic cells

    Immunol Rev

    (2010)
  • M. Collin et al.

    Human dendritic cell deficiency: the missing ID?

    Nat Rev Immunol

    (2011)
  • F. Ginhoux et al.

    Monocytes and macrophages: developmental pathways and tissue homeostasis

    Nat Rev Immunol

    (2014)
  • C.L. Scott et al.

    Mononuclear phagocytes of the intestine, the skin, and the lung

    Immunol Rev

    (2014)
  • S.H. Robbins et al.

    Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling

    Genome Biol

    (2008)
  • A. Bachem et al.

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

    J Exp Med

    (2010)
  • K. Crozat et al.

    The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells

    J Exp Med

    (2010)
  • S.L. Jongbloed et al.

    Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

    J Exp Med

    (2010)
  • L.F. Poulin et al.

    Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells

    J Exp Med

    (2010)
  • M. Guilliams et al.

    Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny

    Nat Rev Immunol

    (2014)
  • R.M. Steinman et al.

    Taking dendritic cells into medicine

    Nature

    (2007)
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