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Published online before print August 21, 2006
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Centre for Virus Research, Westmead Millennium Institute and University of Sydney, Sydney, New South Wales, Australia
1 Correspondence: Centre for Virus Research, Westmead Millennium Institute, Westmead Hosptial, Darcy Rd., Sydney, NSW 2145, Australia. E-mail: tony_cunningham{at}wmi.usyd.edu.au
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ABSTRACT |
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 TOP ABSTRACT DENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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Key Words: pathogenesis • immune responses
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DENDRITIC CELL SUBSETS |
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TOPABSTRACTDENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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), stimulation of naïve T lymphocyte clonal expansion [2
, 3
], natural killer cell stimulation [4
], as well as having a crucial role in peripheral tolerance to self peptides [5
]. They are derived from CD34+ stem cells via at least 2 generation pathways: myeloid and lymphoid [6
, 7
]. Myeloid DCs (mDCs), characterized by CD1a and CD11c expression, are found in most tissues except the brain and testes [3
]. They are further subdivided into Langerhans cells (LCs) in squamous epithelium; dermal, or submucosal DCs; interdigitating DCs in the T cell areas of the lymph nodes and blood mDCs (CD11c+ CD123-). In addition, DCs can be generated from blood monocytes (known as monocyte derived DCs or MDDCs) or bone marrow precursors [8
, 9
]. In contrast, DCs of lymphoid lineage, commonly called plasmacytoid DCs (pDCs), have a more restricted distribution being found predominantly in the blood (BDCA4+ CD123+) and lymphoid tissues [10
, 11
]. Dendritic cells express different pattern recognition receptors (PRR), depending on the cell subset and probably to some extent on location. These PRR are able to recognize motifs unique to different classes of pathogen [12 ]. The 2 main types of PRR are C type lectin receptors (CLR), which recognize glycosylated carbohydrate domains [13 ] and Toll like receptors (TLR), which have a high degree of specificity for individual pathogen associated molecular patterns [14 ]. A summary of expression of different PRR on DC subpopulations can be found in Table 1 .
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0.5% of mononuclear cells). It is thought that they migrate from the blood to the tissues. However, there is limited information regarding the maturation of a blood DC into a tissue DC [15
, 16
], and more recent evidence suggests that, at least some of these blood mDCs are programmed to migrate directly to the lymph nodes or thymus [16
].
Langerhans cells
Langerhans cells are distributed in the skin, as well as within the stratified squamous epithelia covering the male and female genital tracts (6). They constitute 2-4% of total epidermal cell population. These cells were first described in the skin by Langerhans in 1868, and Steinman first identified cells in the lymphoid tissue of mice that were potent stimulators of primary immune responses [17
]. It was not until much later, however, that LCs were described as a stage of DC development [18
]. Initially identified by the presence of Birbeck granules, LCs are now described as HLA-DR+CD1a+CD4+CCR5+Langerin+E-Cadherin+ DC-SIGN- CD83- (Table 1)
. In mice, they express TLR 2, 4, and 9 but not 7 [19
]. As the most superficially located DCs, LCs are thought to be crucial in the generation of an immune response to cutaneous antigens. However, this may be more complex than previously thought. During herpes simplex virus (HSV) infection, murine skin LCs may carry viral antigen to lymph nodes but then transfer it to CD8+ DCs for presentation to T lymphocytes [20
]. Furthermore, mice lacking epidermal LCs have an enhanced contact hypersensitivity response [21
], suggesting a role of LCs in peripheral tolerance.
Interstitial DCs
The interstitial or dermal DCs are found in most tissues, including the heart, liver, and kidneys, where they are associated with vascular structures [3
]. They lack langerin and Birbeck granules but express CD2, CD9, CD68, the coagulation factor XIIIa, the scavenger receptor CD36, and the CLR DC-SIGN (see Table 1
). In vitro derived dermal DCs were found to have up to 10 times the antigen uptake capacity of LCs [22
].
Model MDDCs
Epidermal and dermal DCs derived freshly from human skin explants are difficult to isolate in high numbers; therefore, a suitable model for in vitro generation of DC is required. Monocytes from blood can be induced to differentiate into monocyte-derived DCs (MDDC) in 5–7 days in the presence of IL4 and GMCSF [8
], and these serve as a convenient in vitro model for DCs. MDDCs express CD11b, CD11c, MHC class II, CD1a, DC-SIGN, and low levels of the costimulatory molecules CD80 and CD86 (Table 1)
and resemble the immature dermal DC subset in vivo. However, they should really be considered a unique in vitro DC phenotype because differences in the levels of expression of CD14, CD1a, and DC-SIGN on in vitro derived MDDC and in vivo dermal DCs exist [23
]. Moreover, MDDC have rarely been identified in vivo in areas of inflammation.
Dendritic cells can also be generated from CD34+ stem cells, which can be readily isolated from umbilical cord blood. Culture of these cells for 5 days in GM-CSF, TNF, SCF, and Flt-3 ligand results in the generation of two cell populations: a CD1a+ CD14- and a CD1a- CD14+ population [24
]. Isolated CD1a+ CD14- cells cultured for a further 5-7 days in GM-CSF, TNF, and TGFß give rise to CD11b, DC-SIGN negative, CD1a Langerin-positive Langerhans-like cells [25
]. Cultured CD1a- CD14+ cells differentiate into dermal-like DCs in the presence of GM-CSF and IL-4 and are negative for Langerin but express CD11b, DC-SIGN, and CD1a [25
]. Our group has generated Langerhans-like cells from peripheral blood monocytes cultured in the presence of IL4, GMCSF, TNF, and TGFß (Dable et al., unpublished results).
Plasmacytoid DCs
The pDCs are both functionally and phenotypically distinct from mDCs, exhibit a more restricted distribution, and have not been subclassified. They lack myeloid markers such as CD13, CD14, and CD33 but do express HLA-DR, CD4, and IL3R (CD123). In addition, they are CD11c negative and CD45RA+ (Table 1)
. They express BDCA4 (neuropilin 1) and BDCA2 [26
], a CLR that can internalize antigens that are subsequently presented to T lymphocytes [27
]. Plasmacytoid DCs express TLR7 and TLR9, intracellular PRR that detect RNA and DNA viruses, respectively, within endosomal/lysosomal compartments following acidification [28
29
30
]. Isolated blood dendritic cells were found to produce more IFN than monocytes in response to several viruses, including HIV and HSV [31
]. Further purification of blood DCs has enabled identification of pDCs as the professional interferon producing cell. Using these purified pDCs, Siegel et al. [11
] showed that these cells produce IFN in response to viruses, including herpes simplex virus (HSV), and it was also shown that these cells produce IFN in response to HIV [32
] and influenza [33
]. Indeed, viruses do not need to be replication competent in order to induce IFN production. In the case of HSV, it seems that an intact envelope is required for endocytosis as UV-inactivated HSV is able to stimulate production, but heat-killed virus is not [28
, 32
, 34
]. However, intact HIV gp120 alone seems sufficient to induce IFN production [31
]. Virally stimulated pDCs have been implicated in the induction of cytotoxic T lymphocytes (CTL) [35
], although these CTL may be regulatory in function [36
].
Plasmacytoid DCs are thought to migrate directly from the blood to the lymphoid tissues and are not found in normal noninflamed tissues. There is evidence to suggest they may move into tissues during inflammatory or allergic conditions [37 , 38 ], although they were not detected in intestinal tissue of Crohns disease patients [39 ].
Dendritic cell maturation and migration
Dendritic cells exist in three distinct stages of maturation; precursors, immature and mature, and their location in the body is dependent on the state of maturation. Precursor mDCs in the blood are believed to migrate to the tissues where they remain in an immature state. This view might oversimplify matters because dermal DCs have been generated from blood mDC precursors [16
]; however, Langerhans cells have only rarely been generated from mDCs. Instead, LCs have been shown to be generated from a dividing precursor population in the skin and these, not blood-derived precursors, may be responsible for maintaining skin LCs [40
, 41
]. Additionally, blood mDC did not differentiate into LC in vitro [16
], while isolated blood monocytes can be differentiated into Langerhans-like cells in vitro (Dable et al., unpublished data). Langerhans cells and dermal DCs as described above are immature DC. Immature mDCs are highly endocytic but less potent immune stimulators. Maturation diminishes endocytosis but increases immunostimulatory function, especially to T lymphocytes. Mature DCs are largely found in the lymphoid tissue, having migrated from site of antigen encounter to the site of T cell stimulation.
Maturation of epithelial DCs is often associated with their emigration to lymphatic tissues and lymph nodes. Immature DCs act as sentinels, sampling the surrounding area for evidence of pathogens. They are highly efficient at antigen uptake, express moderate amounts of MHC class II, and low levels of costimulatory molecules. They express the chemokine receptors CCR1 and CCR5. DCs will mature in response to both endogenous (such as antigen uptake or viral replication in DCs) or exogenous stimuli [including lipopolysaccharide (LPS) or cytokines such as TNF, prostaglandins]. Maturation results in 1) up-regulation of DC adhesion and costimulatory molecules: CD40, CD80, CD83, CD86, and also MHC class II are all up-regulated. The adhesion molecules ICAM-1 and VLA-4 are also up-regulated, which enables more prolonged DC-T lymphocyte interaction [42
, 43
]; 2) modulation of chemokine receptors: CCR7 expression on DC is increased, which induces migration to the secondary lymphoid tissue [44
] in response to CCL21 and CCL4 produced in the lymph node [45
, 46
]. Maturation of DCs results in decreased CCR5 and increased CXCR4 expression in slightly different patterns in LCs and MDDCs in vitro [47
]; 3) secretion of cytokines (IL-12, IL-15, IL-18) and chemokines (MDC, TARC, ELC), which stimulate DC-T cell interactions, which drive helper and cytotoxic T lymphocytes activation [48
]; and 4) modulation of CLR: DC-SIGN, mannose receptor (MR) and to a lesser degree, Langerin are all down-regulated by maturation. This coordinated alteration in DC phenotype and function during maturation ensures that upon entry into the lymph node, the DC is highly specialized at presenting antigen to T lymphocytes.
In addition to the conventional mechanism of DC maturation, it has now been shown that other antigen-presenting mechanisms can be used by DCs. The first of these occurs in the steady state, in the absence of maturation stimuli. DCs spontaneously migrate to the lymph nodes and present self peptides to T lymphocytes. The lack of costimulatory molecule expression on these DCs induces T lymphocytes anergy and contributes to maintenance of peripheral self-tolerance [5 , 49 ].
Resident DCs in the lymph nodes have also been shown to take up soluble antigens that have been applied peripherally. These antigens are expressed in lymph nodes on the surface of DCs in association with MHC class II molecules within a few hours of subcutaneous injection [50 , 51 ]. Migration of DCs to the lymph nodes is believed to take longer than this, probably 12 or more hours. More recently, a mechanism for the delivery of soluble antigens from the periphery to lymph node DCs has been described in which the antigens are transported within the reticular network of lymph nodes [52 ].
Antigen presentation to T lymphocytes
In contrast to the highly endocytic immature DC, a mature DC is a more efficient antigen-presenting cell. Dendritic cells express high levels of MHC molecules on their surface, enabling one DC to interact with multiple T lymphocytes at any one time. Once DCs engage T lymphocytes the MHC class II molecules move to the DC surface from a late endosomal compartment along microtubules [53
, 54
]. The MHC class II molecules are then expressed on the surface within contact regions with T lymphocytes termed the immunological synapse [55
]. Visualization of these DC-T lymphocytes interactions in the lymph nodes have revealed that, in the presence of antigen, DCs form stable, long-lasting contacts with both CD4+ [56
] and CD8+ [57
] T lymphocytes.
The fate of mature DCs once they have interacted with T lymphocytes in the lymph node is not clear. They are not found in the efferent lymph and are therefore thought to undergo apoptosis in the lymph nodes [58 ]. This results in a feedback mechanism, whereby continued migration to the lymph nodes reflects continued antigen stimulation. Once the stimulus has been removed, the migration of mature DCs to the lymph nodes stops and T lymphocyte activation ceases.
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HIV AND DCs |
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TOPABSTRACTDENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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HIV Receptors on DCs
Different DC populations express CD4 and the chemokine receptors CXCR4 and CCR5 to varying degrees [59
60
61
]. They have also been shown to express a diversity of CLRs [24
, 62
].
CD4, CXCR4, and CCR5
Several groups have shown that different DC populations express CD4 and the chemokine receptors CXCR4 and CCR5 to varying degrees [59
, 60
, 63
64
65
66
]. CCR5 genotype is a major determinant of HIV susceptibility, with individuals homozygous for CCR5 containing a 32 base pair deletion being protected from infection. In addition, ex vivo LCs from CCR5
32 homozygotes were less susceptible to HIV infection than LC from wild-type individuals [60
]. The importance of CCR5 in HIV transmission is further delineated by evidence that LCs emigrating from epidermal sheets pretreated with PSC-RANTES, a molecule that binds to CCR5, were resistant to HIV infection in a dose-dependent manner [67
], and topical application of PSC-RANTES prevented vaginal transmission of SHIV in rhesus macaques [68
].
C-type lectin receptors
The function of CLRs is to facilitate endocytosis, and many different CLRs have now been identified on the surface of different DC subpopulations. DC-SIGN (CD209), a CLR found on the model MDDC, has been most intensively studied because it was shown to bind HIV via the highly glycosylated gp120 [69
]. However, in uninflamed tissues, in vivo expression of DC-SIGN is limited to dermal and lamina propria DCs and is not found on LCs in superficial epithelium or on fresh mDCs or pDCs in blood. Epidermal LCs express the CLR Langerin [62
, 70
] which is thought to bind HIV by its mannose-bearing ligands [23
].
Myeloid DCs in noninflamed tonsil and probably lymph nodes express very low to undetectable levels of CLRs (DC-SIGN and MR). However, in inflammatory conditions, cytokine production may result in CLR up-regulation that is, GM-CSF for MR and IL-4 for DC-SIGN [71 ]. A potential role of CLRs and DCs in mucosal lymphatic tissue, lymph nodes, thymus, and placenta in enhancing HIV replication in such inflammatory conditions needs to be examined. DC-SIGN and possibly other CLRs are expressed on DCs in normal uninflamed placenta, thymus, and lung [71 ]. To date, the only CLR found to be expressed by pDCs is BDCA-2 [27 ]
Other CLRs include Dectin1, Dec205, BDCA-2 (expressed by pDC), and DC-SIGNR (a DC-SIGN related molecule). The roles of each CLR in HIV is not fully understood but as they are studied further, it is likely that they will be found to have a role in HIV uptake, especially given recent findings that polymorphisms within DC-SIGNR may influence susceptibility to HIV-1 [72 ].
HIV infection of DC
In 1987, LCs from HIV-1-infected patients were shown to be infected with HIV-1 [73
], and in the same year, Patterson and Knight [75
] showed that crude populations of DC isolated from normal individuals were susceptible to HIV-1 infection in vitro. Several subsequent studies have shown HIV-1 infection of blood DCs in vitro [61
, 75
, 76
] and in vivo [75
, 77
, 78
], while LCs have been found to be infected in vivo [79
, 80
]; splenic DCs showed low levels of infection [81
] and p24+ pDCs have been detected in the tonsil of an HIV-infected patient [76
]. However, uninfected interdigitating DCs were observed in close proximity to SIV-infected cells in lymph nodes of SIV-infected monkeys, suggesting that in this instance, the DCs were not productively infected with SIV [64
].
One feature that these studies share is the low levels of productive infection of DCs when compared with CD4 lymphocytes. In one study, levels of infection of blood DC isolated from patients were estimated at between 0.02 and 0.1% in both mDCs and pDCs, with higher frequencies in T lymphocytes [78 ]. However, even DC infection levels of less than 1% are more than sufficient to provide an explosive viral infection in CD4 lymphocytes [82 ]; indeed, infection of DCs may not be a requirement for the DC to be able to transmit virus to T lymphocytes (see below).
Transfer of HIV from DC to T cells
Sessile immature DCs, such as LCs in the epidermis and interstitial DCs in the dermis, lamina propria or submucosa are likely to be the first DCs to contact HIV (or SIV) following mucosal exposure. HIV may infect epidermal LCs through intact or abraded mucosa and dermal/lamina propria DCs through mucosa ulcerated by other pathogens (such as HSV2) or trauma. HIV probably binds initially to Langerin or DC-SIGN on DC in the genital tract before internalization into endosomal compartments where it briefly retains infectivity [83
].
Work in our laboratory suggests that trans enhancement, which persists for 6 to 12 h with a tail to 24 h after HIV binding, is likely to be an important factor in the local transfer of virus to intraepithelial lymphocytes and possibly, at lower levels to lamina propria T lymphocytes (Fig. 1
). However, because DC migration to lymph nodes requires 12 to 24 h, trans enhancement may not result in large virus dissemination, as the majority of virus is likely to be degraded during this time via the endosomal acidic proteolytic environment in the DC [70
, 84
] (Fig. 1)
.
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In DC-T cell conjugates viewed by live-cell microscopy, the HIV receptors CD4, CCR5, and CXCR4 on the T lymphocyte were recruited to the interface, while the MDDCs concentrated HIV to the same region [88 ] to form an infectious synapse and enhance transmission of HIV. Recently, Lore et al. [89 ] have shown evidence that DC-T lymphocytes conjugates are the primary sites for HIV production and that DCs transfer virus to antigen-specific CD4+ T lymphocytes [89 ]. This correlates with previous work showing that HIV preferentially infects HIV-specific CD4+ T lymphocytes [90 ].
Although trans enhancement may not be critical in viral dissemination in the lymph node, the contribution in the establishment of infection should not be overlooked. Transfer of virus from DCs to T lymphocytes in submucosa (i.e., within first few hours) may help contribute to the development of small founder populations. Indeed, LCs and T lymphocytes are often observed in direct contact in the human cervical and vaginal epithelium [91 ], which could facilitate trans infection of the T lymphocytes with HIV. Ex vivo studies using human cervical tissue indicate that HIV may also be disseminated to draining lymph nodes by migrating CD4+ T lymphocytes [92 ], possibly from submucosal sites [93 ]. Recent evidence that found transmission of HIV from mDC to T lymphocytes in the presence of neutralizing antibody [94 ] suggests that DCs transmit virus to T lymphocytes during an immunological synapse, when the two cell types are closely linked, thereby shielding the virus from neutralization.
Effect of DC maturation on level of HIV infection
There is evidence that the maturation status of the DC affects the susceptibility to infection. Immature DCs are thought to be more susceptible to infection [95
, 96
]. Some reports found that mature DCs were resistant to infection [97
] or that HIV was unable to replicate in mature DCs [47
, 98
], because of a block at the level of reverse transcription [65
]. However, despite higher infection of immature DCs, mature DCs have been shown to be HIV infected, as measured by p24 in the supernatants 7 days after infection [66
]. Interestingly, while some groups have found productive viral infection of unstimulated pDC [61
, 99
, 100
], others show that pDC require postinfection activation for HIV replication [76
].
HIV binds and enters a different compartment in mature to immature DCs [101 ]. HIV is found within a single, large Clathrin-coated compartment in mature DCs that has recently been shown to label for CD9, CD63, and CD81 [102 ]. Virus can be transferred to CD4 T lymphocytes from this compartment in trans. Mature DCs are less endocytic and phagocytic than iDCs, although they retain intact infectious particles within the endosome for longer periods and are more efficient at antigenic stimulation of T lymphocytes and HIV transfer to these cells. Maturation enhances the formation of both immunologic and viral synapses with T lymphocytes. Of note, mature DCs stimulate both CD4- and CD8 HIV/SIV-specific lymphocytes, whereas immature DCs trigger only CD4 lymphocyte responses [103 ]. LFA-ICAM interactions and the tetraspannins are involved in this synapse formation, but the CLRs appear not to be concentrated at the synapse [102 ]. CLRs are essential for uptake of HIV into the endocytic compartment in iDCs. Maturation down-regulates CCR5 and up-regulates CXCR4. After maturation and/or migration, endocytosed virus is transferred with greater efficiency to T lymphocytes than by immature DCs. The ability of HIV to fuse with DC declines with maturation [104 ].
Impact of HIV on DC function
While there may be differences in the level of infection of DCs depending on their maturation status, it is important to consider that HIV exposure affects the ability of DCs to function correctly and may inhibit or alter the generation of immune responses to HIV.
The published literature on the function of myeloid DCs in vitro is somewhat contradictory and requires further clarification (see Chougnet and Gessani in this issue). The reasons for the confusion are probably due to differences in HIV inoculum, purification techniques, and duration of infection.
In short-term in vitro cultures, blood DCs exposed to HIV do not undergo full maturation as determined by costimulatory molecule expression [100
]; however, blood DCs derived from HIV-infected individuals have increased CD86 expression [105
, 106
]. Patient DCs appear functionally impaired, as the ability of patient blood DCs to stimulate T cell proliferation was impaired [78
], and chemokine receptor expression of blood DCs is altered in patients with HIV [107
]. Peripheral blood mononuclear cells from patients have reduced the ability to produce IFN in response to viral stimulation, likely reflecting a dysfunction in pDCs [108
]. In vitro infection of isolated pDCs resulted in maturation and production of large amounts of IFN in contrast to mDCs, which did not mature; however, the HIV-exposed pDCs were able to induce maturation of mDCs [32
]. In another study, however, where a higher inoculum was used, a partial maturation of both mDCs and pDCs was observed, without compromising the ability of DCs to produce TNF in response to further stimulation [100
].
We have found up-regulation of maturation markers by monocyte-derived DCs and ex vivo LCs following in vitro infection with HIV (A. Harman et al, unpublished data). This was clearly dependent on the size of the inoculum. HIV exposure resulted in partial up-regulation of costimulatory molecules, as well as increased CCR7 expression on MDDCs, and migration along a chemokine gradient [109 ]. However, Kawamura et al. [110 ] found that 12 days after HIV infection, p24+ DCs had decreased surface expression of CD4, CD1a, and MHC class 1. When isolated, these p24+ DCs were found to have a reduced allostimulatory capacity and lower IL-2 production compared with uninfected cells. Similarly, Granelli-Piperno et al. [111 ] found that HIV-infected BDCA1+ DCs isolated from blood had reduced capacity to stimulate T lymphocyte proliferation. In addition, IL12 production by DC is impaired in DCs infected with HIV in vitro [112 ]. This may be mediated by vpr, which has been shown to inhibit IL-12 production and enhance IL10 production by DCs in response to CD40L or LPS stimulation [113 ].
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INTERACTIONS OF HIV WITH BLOOD AND LYMPH NODE pDC |
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TOPABSTRACTDENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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production [11
]. Recombinant gp120 has been shown to induce IFN production by pDCs [115
]. However, HIV-infected patients have reduced capacity to produce IFN in response to stimulation with HSV, or influenza and this has been correlated with pDC frequency [116
]. Stimulation of pDC by HIV does not induce as much IFN production as stimulation with HSV [99
]. In response to virus, pDCs secrete chemokines and interferons to prevent infection, but these molecules attract other cells, and this may enhance transmission to other cell types. For example, pDCs produce higher CCL2 (MCP1), CCL3 (MIP1a), and CCL4 (MIP 1b) in response to inactivated HIV than mDCs [115 ]. Secretion of these chemokines may enhance T lymphocyte migration.
Plasmacytoid DC interactions with HIV in the thymus and brain are described below.
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INTERACTIONS OF HIV WITH SPECIALIZED MYELOID DC IN DIFFERENT ORGANS |
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TOPABSTRACTDENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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Early studies provided conflicting reports regarding the ability of DCs from HIV-1-infected patients to stimulate T lymphocyte proliferation [75 , 120 ]. More recently, both mDCs and pDCs of HIV-infected individuals were shown to have reduced capacity to stimulate allogeneic T lymphocyte proliferation [78 , 121 ].
Skin
Reduced numbers of LCs in the skin of HIV-infected individuals has been reported [65
, 123
]. However, others found no difference in LC numbers in patients and controls [124
].
Genital tract
Female genital tract
The human female genital tract is mostly composed of stratified squamous epithelial (SSE) cells, interspersed with both LCs and interstitial DCs. The superficial LCs are likely to be the first DCs to contact HIV. They are found in higher frequencies in the ectocervical epithelium than in the vaginal epithelium with dendrites that reach toward the luminal surfaces. Whether these dendrites are exposed in the lumen of the vagina as in the murine colon [124
] is debatable. Ulceration or abrasion, caused by the trauma of intercourse (microabrasion or full breach) other genital tract pathogens, especially HSV 1 and 2, results in breaches in epithelial integrity allowing direct access of the virus to underlying DCs in the lamina propria, whereby they can transport virus to mucosal lymphoid tissue or lymph nodes.
Although several mechanisms have been proposed to transfer virus across the mucous membranes, such as direct infection of epithelial cells and transmigration of infected macrophages and T lymphocytes from the lumen, there is evidence in macaque and mouse models that uptake of HIV/SIV by DCs may be important in intact and breached mucosa [92 , 93 ].
Male genital tract
The majority of work on sexual transmission of HIV focuses on male to female transmission; however, the glans penis and inner foreskin of men are rich in LCs, which may facilitate entry of virus [125
] in female to male transmission. A recent report of reduced HIV transmission in circumcised men may reflect the role of LCs in male sexual transmission [126
].
Lymph node and spleen
During acute HIV-1 infection, the numbers of DCs in the lymph nodes were found to be raised compared with HIV-1 negative individuals [127
], suggesting that the reasons for the loss of DCs from the blood and skin may be due to migration to the draining lymph nodes (at least during primary infection). However, such migration cannot account for all of the loss in circulating DCs as patients with AIDS had a reduced number of DCs in the lymph node [127
]. Indeed, the migration of LCs was found to be normal in monkeys infected with SIV but was impaired in monkeys with AIDS [64
, 128
], accounting for the reduced numbers in the lymph nodes of patients with AIDS [127
]. DCs in lymph nodes failed to mature, characterized by incomplete up-regulation of CD80 and CD86 [127
], which, in turn, limited the generation of HIV-1-specific CD4 T helper lymphocyte responses. In monkeys with AIDS, the proportion of lymph node DCs was similar to uninfected monkeys, but the cells had lower expression of CD83 [128
]. In normal macaques, DCs in sinusoidal, marginal zone, and indigitating DCs were stained for DC-SIGN, and these cells appear to be absent or down-regulate their DC-SIGN in SIV-infected macaques [129
]. Follicular DCs, nonhematopoeitic cells found in the germinal centers of secondary lymphoid organs are not productively infected with HIV [130
] but are known to trap HIV particles that remain infectious in vivo for more than 9 months [131
]. In a sequencing study, this cell-free HIV appears to be produced locally [132
], corresponding to data showing a shorter half-life of the virus when patients start antiretroviral therapy [133
].
Thymus
CCR5 tropic viruses are predominant in early infection, and the appearance of X4 viruses tends to indicate disease progression. In vitro, both R5 and X4 viruses replicate in thymic pDCs [134
], while in thymocytes CXCR4 tropic viruses replicate more efficiently than R5 tropic viruses [135
], and mDCs preferentially replicate R5 viruses [134
]. A situation like this where X4 and R5 virions are produced and transmitted to thymocytes may enhance X4 virion numbers and contribute to the switch in coreceptor usage. Furthermore, pDCs in the thymus secrete IFN- in response to HIV, which, in turn, drives up-regulation of MHC class I on thymocytes, leading to generation of CD3+CD8lo thymocytes, which were less responsive to stimulation [136
, 137
], leading to the proposal that pDC-derived IFN- in the thymus may be detrimental to the generation of effective CD8 T lymphocytes in HIV.
Brain
Although, under normal circumstances there are no DCs in the brain, some inflammatory stimuli can recruit pDCs to the brain parenchyma [138
]. Both mDCs and pDCs have been found in the cerebrospinal fluid and choroid plexi under normal conditions and during inflammatory disease [139
, 140
] and may enter brain during inflammatory conditions such as multiple sclerosis [141
]. In the choroid plexes from HIV-infected asymptomatic patients, as well as those with AIDS, there is direct infection of both stromal macrophages and DCs. As viral sequences obtained from the choroid plexi are similar to those found in both brain and blood [142
], it has been suggested that choroid plexi may form one avenue for access of HIV to the brain.
Gut
Interstitial DCs expressing DC-SIGN are abundant in the lamina propria and submucosa of the gut and rectum [143
]. In SIV macaque models, there is productive infection of macaque intestinal DCs, especially those expressing DC-SIGN [143
]. During SIV infection, the DC networks remain intact, and there was apparently an increased expression of DC-SIGN. In the rectum, there are no HLA-DR cells in the epithelium [126
]. However, DCs expressing DC-SIGN, CD4, and CCR5 were localized just beneath the luminal epithelium, indicating their susceptibility to HIV infection [144
].
Placenta
In the placenta, DC-SIGN is expressed on maternal decidual macrophages, as well as fetal Hofbauer cells [145
]. Separating these 2 macrophage-like cells is the trophoblast, and any inflammation or abrasion would allow maternal decidual macrophages and fetal Hofbauer cells to come into contact with each other. The expression of DC-SIGN on these cells and CD4 and CCR5 on Hofbauer cells [145
] may enable transmission of HIV from mother to child across the placenta.
Lungs
Both mDCs and pDCs have recently been isolated from bronchoalveolar lavage fluid [146
], although the role of lung DC in HIV infection has yet to be investigated.
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CONCLUSIONS |
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TOPABSTRACTDENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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ACKNOWLEDGEMENTS |
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Received March 4, 2006; revised April 12, 2006; accepted May 17, 2006.
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REFERENCES |
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TOPABSTRACTDENDRITIC CELL SUBSETSHIV AND DCsINTERACTIONS OF HIV WITH...INTERACTIONS OF HIV WITH...CONCLUSIONSREFERENCES |
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cooperate in the generation of dendritic Langerhans cells Nature 360,258-261[CrossRef][Medline].2. Functional analysis Blood 90,1458-1470 in response to HIV-1 infection J. Immunol. 152,4649-4662[Abstract]
