Dendritic Cells (DCs) are important members of the mammalian immune system. Working at the interface of innate and adaptive immune response, DCs are primarily antigen-presenting cells (APCs). DCs are derived from certain hematopoietic (bone-marrow derived) progenitors of either lymphoid or myeloid lineage, giving rise, respectively, to plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) that localize to mucosal epithelium (inner lining of nose, lungs, the GI tract; also, the langerhans cells of the skin), as well as to peripheral blood.

Immature/resting DCs engage in continuous surveillance, i.e. they sample the surrounding by taking up substances via a process called endocytosis. Ordinarily, this doesn’t lead to subsequent immune events, such as activation of T-cells (in fact, immature DCs are characterized by high endocytic activity and low T-cell activation potential). However, when microbial pathogens (viral, bacterial or fungal) or pathogen by-products or antigens are present, those are recognized by various specialized molecules present on the DC surface, such as pattern recognition receptors (e.g. the Toll-like Receptors/TLRs 2, 4, 7 and 9, or the carbohydrate-binding protein called DC-SIGN), receptors for certain components of the complement system, and the FcγR (a protein that can bind the Fc portion of antibodies); these structures help the DCs phagocytose (capture and internalize) the pathogen, which are then degraded into smaller pieces and processed for the purpose of presentation of the antigen on the cell surface, in conjunction with another set of specialized molecules, called the MHC.

This marks the maturation/activation of the DCs, which then migrate to the lymphoid tissues, presenting the antigens to naive T-cells. Upregulation of various costimulatory molecules in mature DCs enhances their T-cell activation capabilities. DCs may also secrete certain cytokine mediators – which may act as maturation signals – in response to specific pathogenic components; for instance, mDCs in lungs respond to inhaled spores (“conidia”) of the mold Aspergillus by inducing IL12, and to Aspergillus hyphae by inducing TNFα, IL4 and IL10.1

As APCs, DCs are potent activators of both naive and memory T-cells, and are, therefore, vital to antiviral defence. For example, pDCs express high levels of TLR7 and TLR9, which recognize single-stranded RNA (as present in RNA viruses, such as influenza) and unmethylated DNA with CpG motifs (as present in DNA viruses, such as HSV-1 and 2), respectively.

However, certain viruses, including the HIV-1, have evolved strategies to evade the antiviral activity and subvert the function of the DCs to their own ends. HIV can enter the DCs by being passively taken up via endocytosis — either by interaction of the HIV envelope glycoprotein gp120 with surface receptors,2 or via a glycoprotein-independent, cholesterol-dependent mechanism involving a cellular structure called exosomes.3

Exosomes, membrane-bound structures which normally carry antigens to DCs, are budded off by certain cells, including other APCs or infected cells, from specialized locations on the membrane, called cholesterol-enriched membrane microdomains. HIV particles are able to mimic the exosomes, and they enter the DCs following the same pathway. Once inside, the virus is able to put itself in a safe compartment, thereby evading the classical lysosome-mediated mechanisms of destruction and degradation, as well as subsequent antigen processing and presentation.4 When the unsuspecting CD4+ T-cells interact with the HIV-carrying DCs, the virus infects them. This is known as DC-mediated HIV-1 transmission to (or trans-infection of) CD4+ T-cells.3

HIV mimicking exosomes in using DC to infect T-cells

Image reproduced from Figure 7b of Izquierdo-Useros et al, 2009 [3].

The 2009 study by Izquierdo-Useros3 made another interesting observation: if the cells giving off exosomes or the virus are treated with certain substances that inhibit the synthesis of a lipid molecule called sphingolipid, entry of the particles (exosomes or virus) into DCs were significantly reduced. Further studies into the molecular determinants of the process which allows HIV to use DCs as Trojan Horses to infect T-cells may help devise strategies to defeat HIV and other retrovira.

Further Reading

  1. Bozza S, Gaziano R, Spreca A, Bacci A, Montagnoli C, di Francesco P, & Romani L (2002). Dendritic cells transport conidia and hyphae of Aspergillus fumigatus from the airways to the draining lymph nodes and initiate disparate Th responses to the fungus. Journal of immunology (Baltimore, Md. : 1950), 168 (3), 1362-71 PMID: 11801677
  2. Turville SG, Cameron PU, Handley A, Lin G, Pöhlmann S, Doms RW, & Cunningham AL (2002). Diversity of receptors binding HIV on dendritic cell subsets. Nature immunology, 3 (10), 975-83 PMID: 12352970
  3. Izquierdo-Useros N, Naranjo-Gómez M, Archer J, Hatch SC, Erkizia I, Blanco J, Borràs FE, Puertas MC, Connor JH, Fernández-Figueras MT, Moore L, Clotet B, Gummuluru S, & Martinez-Picado J (2009). Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood, 113 (12), 2732-41 PMID: 18945959
  4. Kwon DS, Gregorio G, Bitton N, Hendrickson WA, & Littman DR (2002). DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Immunity, 16 (1), 135-44 PMID: 11825572