Dendritic Cells (DC)

R.M. Steinman (Canada, USA) won the 2011 Nobel Prize for his discovery of the dendritic cell and its role in adaptive immunity.

Dendritic cells (DC) are distinguished from the human mononuclear phagocyte system by their outgrowth or dendrite morphology, high levels of Class I and Class II HLA molecules expression, and properties of superior migration, antigen presentation, and activation of naive lymphocytes. Currently, there have been rapid advances in understanding the ontogeny, heterogeneity and functional specialization of DC subsets in mice but relatively little is known about the ontogeny, differentiation, and activity of human DC subsets. DCs are a heterogeneous cell population taking into account their origin, locations, phenotypes, and immunological functions. Though this cell type was discovered by 2011 Nobel Laureate R.M. Steinman, but one subset, Langerhans cells, was revealed in 1868 by P. Langerhans.



Immature DCs

Mature DCs

   HLA molecules   (+)   +++
   (except follicular DCs)
   Costimulatory molecules: CD80, CD86, CD40, etc   (+)   +++
   CD83+ marker   -   ++
   CCL21/CCR6, CCR7
   ++   -
   CCL3/CCR1, CCR5
   CCL5/CCR1, CCR3, CCR5
   -   ++
   Antigen endocytosis   +++   (+)
   Antigen presentation   +   +++
   Number of dendrites   +   +++
   Presence in the blood   0.1-0.5%   -

All DCs are capable of pathogen engulfing, processing and antigen/Class I or Class II HLA complex presenting to lymphocytes. Immature DCs function through the uptake and accumulation of any antigens at the skin and mucosal level, whereas mature DCs take part in antigen presentation and initial stages of adaptive immune responses in the secondary lymphoid organs. They also can initiate the induction of immunological tolerance. Most described DCs express PRR to recognize molecular patterns as well as receptors for cytokines and chemokines and upregulate reactions of the innate immunity. To date, some functional and morphological subsets of the DCs have been described in humans.

Langerhans cells originate from the yolk sac and fetal liver's monocytes. These DCs can be identified by the presence of langerin/CD207-containing Birbeck granules as well as the expression of Class I and Class II HLA molecules and CD1ahi. Langerhans cells are located in the epidermis and mucosal epithelium, may uptake antigens, migrate to SALT and MALT-draining lymph nodes, and initiate the T-cell-mediated immune responses.

Type 1 myeloid (myeloid or conventional DCs) (mDCs/cDCs) are myeloid progenitor-derived DCs involved in T-cell-mediated responses. They subdivide into two subtypes:
(1) the major DCs subset (mDC-1), CD141+, which mainly express Class II HLA molecule and may activate like macrophages naïve CD4+T cells to clonal expansion, differentiation and immune inflammation, and
(2) a rarer DCs subset (mDC-2), CD1c+, which express Class I and Class II HLA molecules, capable of cross-presentation and may activate both naïve CD4+ and CD8+T cells.
Both subtypes possess characteristic long outgrowths called dendrites required for antigen presentation and secrete IL-12 and other pro-inflammatory cytokines. Mature mDCs are described as interdigitating DCs, which are resident in the secondary lymphoid organs. If any mature DCs are located in the barrier organs, they are interstitial DCs. Thymic DCs in the thymus are closer to interdigitating DCs (mDCs).

Type 2 plasmacytoid DCs (pDCs) are lymphoid progenitor-derived DCs that in the immature state are characterized by spherical morphological features similar to plasma cells. In the mature state, they acquire conventional DC-like morphology with dendrites, express Class II HLA molecules, CD303+ and CD304+, and secrete IFN-α, IFN-β, TNF-α, IL-6, and IL-12. It is likely that pDCs are involved in the B-cell-mediated response and antiviral defense.

Follicular DCs (fDCs), a distinct subset, appear to arise from mesenchymal progenitor cells. They are located in lymphoid follicles of the lymph nodes, spleen and MALT, have dendrites and high expression of complement receptors CR1 (CD35), CR2 (CD21) and FcγRIIb (CD32) that allow them to serve both as a depository for antigens and as a source of the continued activation for the B-cell-mediated response. The major fDC function is to bind and retain antigens by linking to complement and immune complexes and then present these antigens to germinal center B cells that drive the secondary immune response. However, fDCs never express HLA molecules and cannot initiate the primary immune response.

Inflammatory DCs differentiated from monocytes drive inflammation wherever it proceeds, at inflammatory sites.

Tolerogenic DCs (tDCs) originate from immature DCs, are detractors of antigen-presenting and inflammatory DCs since they take part in immune/allergen tolerance maintenance.