Dendritic Cells (DCs)

Dendritic cells (DC) are a specialized class of leukocytes. DCs and/or their precursors are present as a loose cellular network in the skin (langerhans cells), mucosa, intestines, liver, lung, thymus and most abundantly in the T-dependent areas of lymphoid organs, as well as a minute circulating population in the peripheral blood. In addition to their presence in the normal tissues, where they are thought to serve as sentinel cells that interrogate invading pathogens and monitor cellular changes, DCs have been frequently found to infiltrate neoplastic tissues. Importantly, high natural or therapy induced frequencies of tumor-infiltrating DCs have been associated with better clinical prognosis and/or regression of disease.

Antigen presenting cells, in particular DCs, really orchestrate the immune response.

Subsets of DCs

DC markers/receptors

Cytokines produced by DCs

Where are DCs Found

Spleen: contains four DC subsets drived from blood precursors (plasmacytoid DCs and 3 conventional DC subsets), all of which constituitvely present self atnigens while, in the staedy state, maintaining an immature phenotype.

Lymph nodes: contain the DC subsets of the spleen as well as migrating DCs (e.g., Langerhans cells) which continually traffic to the lymph nodes and there express a mature phenotype, even in germ free mice.

Morphology and other characteristics

DCs are irregularly shaped cells that display cell processes. DCs do not divide in culture, even after stimulation with LPS or concanavalin A, or in vivo, indicating that they are multipotential end cells, with the ability to mature. In contrast, LCs divide in the epidermis and exhibit mitotic figures.

Functions of DCs

Dendritic cells are leukocytes that are specialized to capture antigens and initiate T-cell-mediated immune responses. There are involved in the following immune functions:

• T-cell Priming      The most unique function of DCs is their ability to prime naive T cells (i.e., to stimulate a primary immune response, while macrophages and other antigen-presenting cells are involved mainly in the expansion of activated T cells. A membrane protein of murine DCs that is structurally homologous to the macrophage mannose receptor internalizes ligand via coated pits and vesicles for delivery to a mutivesicular endosomal compartment containing MHC class II proteins. This process increased by 100 fold the efficiency of antigen presentation to TH cells. Thus DCs Induce, shape and amplify adaptive immunity

Interestingly, mice bone marrow derived DCs which are cultured under different cytokine conditions have functional differences in their ability to stimulate T cells. For example, DCs cultured with Th1 inducing cytokines (IL-12 and IFNy) in addition to GMCSF + IL-3 expressed high levels of MHC class I, class II, CD40, B7.1 and B7.2, showed enhanced IL-12 production and supported the differentiation of IFN-y producing Th1 cells. In contrast, DCs cultured with Th2 inducing cytokine (IL-4) in addition to GMCSF + IL-3 showed reduced production of IL-12 production and as well as costimulatory molecules and did not support differentation of IFNy producing Th1 cells but did enhance differentiation of IL-4 producing Th2 cells.

DCs are equally important in priming naive CD8+ T cells. In vitro, DCs can stimulate the proliferation of allegenic CD8+ T cells, directly in the absence of T cell help.

• Activation of B lymphocytes: Beside activating naive T cells, DCs can directly activate naive and memory B cells. DCs enhance differentiation of CD40-activated memory B cells toward IgG secreting cells through secretion of the solbule IL6Rα gp80, which complexes to IL-6. DCs also help the differentiation of activated niave  B cells to plasma cells.
• Role in Innate Immunity: DCs can regulate effectors of innate immunity such as NK cells and NKT cells. DCs can become cytotoxic and consequently exhibit natural killer function, themselves. DCs also secrete innate immunity soluble factors such as IL-12. Although most cells are able to produce low amounts of INF-α in response to viral infection, the cell population called natural interferon producing cells (IPCs) that is able to produce large amounts of INF-α corresponds to a DC subpopulation in most viral infections.
• Cytotoxic functions: Cytotoxicity has been documented with DCs. This cytotoxitiy was reported to be mediated by death ligands synthesized by DCs: (1) a ligand for Fas induces T cell apoptosis in mice; (2) an unidentified death ligand mediates tumor cell apoptosis in rats and (3) TRAIL induced tumor cell apoptosis in humans. Human immature DCs may directly mediate apoptosis of a diverse array of tumor cells, but not of normal cells. Human immature DCs express TNF, lymphotoxin (LT)-alpha1, beta 2, Fasl, and TRAIL, and kill cancer cells by the concerted engagement of all four cytotoxic TNF family ligands.
• Induction of tolerance: DCs also prevent the immune system from attacking self-components. Two mechanisms exist to accomplish this; central and peripheral tolerance.

• Role in HIV Infection: DC are suggested to play an important role in sequestering HIV from its entry portal at mucosal sites to lymphoid organs. By DC, HIV is shuttled to the LT, where the virus is transmitted to its primary targets, CD4+ T cells.

How DCs take up antigen

DCs select potential T cell antigens by taking up microbial glycoconjugates through specialized receptors. Immature DCs can take up particles and microbes by phagocytosis. They can also form large pinocytic vesicles in a process called macropinocytosis. Thids, they express receptors that mediate adsorptive endocytosis, including C-type lectin receptors like the macrophage mannose receptor, DEC-205, as well as Fc gamma and Fc epsilon receptors.

The antigen enters the endocytic pathway of the cell.

Activation of DCs

Activation of DCs happens mostly through engagement of Toll-like and other pattern-recognition receptors. The type of DCs presenting the antigen and the conditions under which the response is initiated determine the class of immune response elicited and its outcome.

Differentiation/Maturation of DCs

DCs and Antitumor Therapy

A DC vaccine is defined as DCs loaded with antigen, such as a tumor associated antigen. Upon administration into patients, the vaccine is thought to induce an antigen-specific T-cell response against the tumor. Immunization using DCs pulsed with purified tumor-associated peptides or proteins has been shown to be a powerful method of priming tumor-reactive T cells and inducing host protective and therapeutic anti-tumor immunity in mice and humans.

Depletion of either CD4+ or CD8+ T cells from tumor-bearing animals before therapy totally suppresses the therapeutic efficacy of DCs. The antitumor effect is also dependent on the Th1 pathways as administration of antibodies towards Th1 cytokines blocks the anti-tumor effect of DCs.

DCs and HIV infection

The main HIV contamination route is mucosal, and Langerhans cells and interstitial DCs are the main candidates as ports of entry for the virus. DCs express the CD4 receptor for HIV like monocytes, the CCR5, CXCR4 and CCR3 co-receptors, as well as surface lectins. Among these lectins, DC-SIGN binds HIV, activates resting T lymphocytes through ICAM-3 interaction and mediates CD4+ T lymphoctye trans-infection in vitro. Other surface lectins may also play as HIV receptors, including langerin on Langerhans cells and the mannose receptor.

Maturing DCs downregulate CCR5 expression and upregulate CSCR4, thereby becoming less susceptible to the R5-HIV-1 isolates that use CCR5 as co-receptor for viral fusion. After transmission, early existing HIV-1 isolates are almost invariably of the R5-phenotype. This selection for F5-virus strains might depend on the primary contact HIV-1 has with the CCR5-expressing DCs and CD4+ T cells residing at sites of infection. However, the selection of R5-virus may cocur without involving mucosal DCs or T cells. Mucosal epithelia cells, although resistant to virus infection, can bind these viruses and translocate them into contact with submucosal DCs and CD4+ T cells that can further spread the virus within the host. The efficient selection of R5-virus may therefore be due to the fact that epithelial cells, CD4+ T cells and CDs all express CCR5 and are located at the sites of initial infection.

During HIV infection, a strong defect in T-cell proliferation and Il-2 secretion, as well as often IFN-γ production is found in HIV specific T lymphocytes.

Virus loaded DCs have been shown to efficiently induce virus specific CTL HIV virus responses.

Immunosuppressive Drugs of DCs:

Many immunosuppressive and anti-inflammatory drugs target DCs in defined way. Corticosteroid and vitamin D receptor ligands are potent inhibitors of DC differentiation and maturation.

resveratrol: In BM DCs, resveratrol reported inhibited the expression of costimulatory molecules (CD80 and CD86) and major histocompatibility complex (MHC) classes I and II significantly. Resveratrol also significantly suppressed the ability of BM-DC to produce IL-12 p40/p70 and secretory IL-12 p70 in response to LPS stimulation. Resveratrol-treated DC were highly efficient in antigen capture via mannose receptor-mediated endocytosis. Also, they were poor stimulators of naive allogeneic T cell proliferation and induced lower levels of IL-2 in responding T cells.

Rapamycin targets antigen uptake and maturation of DCs.

Chloroquine interferes with endosomal antigen processing and mycophenolate mofetil (MMF)

Acetylsalicylic acid (aspirin) has been shown to supress DC maturation.

Sanglifehrin A, a new cyclophilin binidng immunosuppressant blocks production of IL-12, whithout affecting the phenotypic maturation of DCs.