Dendritic Cell Research

Overview

Dendritic cells (DCs) constitute a diverse set of hematopoietic cell types that play important roles in innate and adaptive immunity.1-3 They are potent antigen sensing and antigen presenting cells (professional APCs) that are uniquely capable of initiating primary immune responses to foreign antigens while safeguarding tolerance to self antigens.4 DCs guide the specificity, magnitude and polarity of immune responses. Because of their instrumental role in the immune system and their natural adjuvant properties, there is great interest in exploiting DCs to develop immunotherapies for cancer, chronic infections and autoimmune disease, as well as for induction of transplantation tolerance.5-7 Accordingly, there is increasing research activity, both in the intricacies of basic DC biology, as well as in murine models of disease and the application of this knowledge to preclinical strategies for the manipulation of DCs in human disease.


 

Dendritic cell maturation

Immature DCs arise from progenitor cells in the bone marrow and migrate to practically all lymphoid and nonlymphoid tissues throughout the body, including the skin, lungs and intestines.8,9 A diverse array of transcription factors, signaling molecules, growth factors, cytokines, chemokines and adhesion receptors has been implicated in the differentiation pathway from common DC progenitors to mature DCs.1,10,11 In addition, through diverse assortments of surface pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), immature DCs receive and process further maturation signals by discerning damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) in their local environments.1,5,7,12 This sensing of damaged cells or pathogens allows DCs to carry out their sentinel-like functions to maintain the body’s integrity.

Maturing tissue DCs alter their surface chemokine receptor and adhesion molecule profiles according to microenvironmental cues and home in to secondary lymphoid organs in response to chemotactic signals. Within lymphoid tissues, immature resident or incoming nonresident DCs can be further stimulated and differentiate to become mature, functional DCs. Mature DCs have advanced capabilities to process and present antigens in the context of self-MHC antigens to naïve CD4+ or CD8+ T cells. This leads to either initiation of primary immune responses against foreign antigens or downregulation of potential T-cell reactivity directed against self antigens. Mature DCs stimulate naïve T cells through their increased surface expression of peptide-loaded major histocompatibility complex (MHC) antigens, costimulatory (or coinhibitory) receptors and ligands, for example, CD80 and CD86, and the release of cytokines such as IL-6, IL-12p70 or interferons (IFNs).1,3,10,11 T cells can further tune the nature of mature DCs. Responding T cells may reciprocally regulate DCs, for example, through CD40-CD40L interactions or by T-cell–derived cytokines such as IL-4 or IFN-γ. In this way, T cells may additionally instruct the professional APCs, which can promote different types of T-cell–dependent immunity or tolerance.

 

Multifunctional roles of dendritic cells

Not only are DCs potent initiators of immune responses, they also play important regulatory roles in determining the type, magnitude and duration of immune responses that ensue.1,4,10,11 DCs accomplish this by their differential expression of cell surface ligands and receptors as well as by secreting distinct profiles of cytokines, chemokines and inflammatory mediators. For example, DCs that release IL-12p70 may preferentially promote type-1 CD4+ T-helper cells (Th1) or cytolytic CD8+ T cells. Other DC types may promote T-cell–dependent humoral or cell-mediated immune responses characteristic of Th2, Th9, Th17, Th22, T follicular helper (Tfh) or regulatory T (Treg) cells. The issue of exactly which DCs orchestrate these types of T-cell–dependent immune responses, and how they do it, remains open and intensively investigated.

Some studies point to the DC’s maturity level as crucial, whereas others point to the major influence of the pathogen type or the tissue site involved. These are all critical parameters that require careful study. The truth may lie somewhere in between, since there is such a large degree of functional plasticity within the DC pathway.2-4,8,11,13,14 The essential link that DCs provide between innate and adaptive immunity is also becoming more appreciated. Not only do DCs mature in response to danger signals, thus becoming capable of inducing a productive T-cell response, they also trigger natural responses to invading infectious agents by activating macrophages, natural killer (NK) cells, natural killer T cells (NKT cells), granulocytes and mast cells.15 The discovery that plasmacytoid DCs (pDCs) are a major source of IFNs, quickly secreting them in response to certain viruses,10 serves as an important example of the multifunctional role played by DCs in both innate and adaptive immune responses.

 

Dendritic cell heterogeneity

Multiple types of precursor, immature and mature DCs (for example, Langerhans cells, dermal or interstitial DCs, blood DCs) that differ in origin, morphology, localization, maturation state, phenotype and function1-4,8,10,11,16 have been described. Despite some cell surface phenotypic differences between the two species, two generally accepted types of DCs have been described in human and mouse model systems that appear to represent different lineages: plasmacytoid DCs (pDCs) and myeloid DCs (mDCs), also known as classical or conventional DCs (cDCs).1,11,13,14 pDCs have a tremendous capacity to produce IFNs but may not present antigens as efficiently as mDCs.1,3,10 Human pDCs are distinguished by their coexpression of CD123 and CD304 whereas mouse pDCs express CD45R/B220 and Ly-6C.1,10,11 Two major classes of mDCs have been further classified in the human and mouse species, which are defined by the alternative expression of either IFN regulatory factor 4 (IRF4+ DCs) or IRF-8 (IRF-8+ DCs).11 IRF4+ DCs in humans characteristically express CD1c, whereas mouse counterparts express either CD4 (lymphoid resident DCs) or CD11b (migratory DCs). The IRF4+ DCs from both species coexpress CD172a/Sirp-α and can efficiently present antigens to naïve CD4+ T cells. Conversely, human IRF8+ DCs typically express CD141, while mouse equivalents express CD8a (lymphoid resident DCs) or CD103 (migratory DCs) with all subsets expressing the XCR1 chemokine receptor, CD370/Clec9a, and capable of presenting antigen to CD4+ T cells and CD8+ T cells. Human and mouse Langerhans cells (LCs) likewise coexpress several distinguishing markers in common including CD207/Langerin, CD326/EpCAM, and CD324/E-Cadherin.1,11,13,14 DC subsets residing in the dermis and intestines of both species have also been described.1,11,16-18 For a summary of human and mouse DC counterparts, see Table 1.

Another class of DCs, inflammatory DCs, may arise from monocytes that may be driven by environmental stimuli to take on the characteristics and functions of DCs.1 Clearly, provocative interspecies differences as well as similarities in certain functionally related molecules are being described for the various DC subsets including their expressed profiles of TLRs, CLRs, CD1 molecules, chemokine receptors and their cytokine secretion patterns.1,6,7 Since a combination of factors, including the DC subset and maturation stage, influence resulting T-cell responses, detailed phenotypic analysis combined with functional studies will be one of the useful approaches in further studying the intricacies of DC biology in physiological as well as pathological conditions.

 

Table 1. Functionality of human DC subsets and their mouse DC counterparts

Human DC Subsets Mouse DC Counterparts Frequency Localization Cytokine Production Upon Stimulation1
pDC pDC ~1% peripheral blood mononuclear cells (PBMCs) Human blood
Lymph node T-cell zone
Tonsil
IFN-I+, IFN-III (IFN-λ)+
IL-6+, IL-8+
IP-10 (CXCL10)+
TNF+
CD1c+ DCs CD4+ or CD11b+ DCs ~1% PBMCs Human blood
Nonlymphoid tissues:
skin, liver, lung and gut
Lymphoid tissues:
spleen, lymph nodes
IL-1β+, IL-6+, IL-8+
IL-10+, IL-12+
IL-23+
TNF+

IL-15+ (skin)
CD141+ DC CD8+ or CD103+ DCs 0.03% PBMCs
CD8+ DCs: 20–40% of mouse spleen and lymph node cDCs
Human lymph node, tonsil, spleen, bone marrow
Human nonlymphoid tissues:
skin, lung, liver, intestine

CD8+ DCs: Mouse lymphoid tissues
IFN-I+, IFN-III (IFN-λ)+
IL-12+ (mouse)
CXCL-10 (IP-10)+
TNF+2
LCs
(Langerhans Cells)
LCs
(Langerhans Cells)
3-5% epidermal cells Human stratified squamous epithelia,
draining lymph nodes
IL-15+
Inflammatory DCs Inflammatory DCs   Inflammatory sites IL-1β+, IL-6+
IL-10+, IL-12+, IL-23+
TNF+

1Cytokine production could vary with the stimulant used, the stimulation conditions or the physiological state of the cell.

2TNF is not typically produced by human CD141+ DCs in response to TLR8 stimulation.


References

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  16. Malissen B, Tamoutounour S, Henri S. The origins and functions of dendritic cells and macrophages in the skin. Nat Rev Immunol. 2014;14:417-428.
  17. Henri S, Poulin LF, Tamoutounour S, et al. CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J Exp Med. 2010;207:189-206.
  18. Klechevsky E, Morita R, Liu M, et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity. 2008;29:497-510.


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