Skin-Derived Dendritic Cells Induce Potent CD8+ T Cell Immunity in Recombinant Lentivector-Mediated Genetic Immunization

He, Yukai; Zhang, Jiying; Donahue, Cara; Falo, Louis D.

doi:10.1016/j.immuni.2006.03.014

Cited by 170 publications

(173 citation statements)

References 65 publications

(98 reference statements)

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“…As these mechanisms are similar to vaccinia virus infection of DC, it is possible that this is a common mechanism shared by epitheliotropic cytopathic viruses that interfere with DC maturation and survival [3]. Whatever the mechanism, our results suggest direct cell-to-cell (or DC-to-DC) contact may be required for this exchange to occur.…”

Section: Subsets In Innate and Adaptive Immunity To Hsvmentioning

confidence: 59%

“…While not disputing the above hypothesis, other studies indicate that the antigen transfer may also occur adjacent to the site of infection and subsequently activate CD4 1 T lymphocytes in the lymph node [12]. Therefore, there may be different locations of antigen uptake/transfer to DC for stimulation of CD4 1 or CD8 1 T lymphocytes.As these mechanisms are similar to vaccinia virus infection of DC, it is possible that this is a common mechanism shared by epitheliotropic cytopathic viruses that interfere with DC maturation and survival [3]. Whatever the mechanism, our results suggest direct cell-to-cell (or DC-to-DC) contact may be required for this exchange to occur.…”

mentioning

confidence: 59%

“…However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7].…”

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confidence: 99%

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Langerhans cells and viral immunity

2008

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Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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Section: Subsets In Innate and Adaptive Immunity To Hsvmentioning

confidence: 59%

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confidence: 59%

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confidence: 99%

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Langerhans cells and viral immunity

2008

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“…An important caveat, however, is that HSV infection is lytic, known to induce DC apoptosis [24] and liberates many apoptotic cell particles that may travel as free material into the LN. Antigens from non-lytic viruses such as lentiviruses are directly presented by skin-derived DC and not CD8a 1 DC [25]. …”

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confidence: 99%

Insights into Langerhans cell function from Langerhans cell ablation models

2008

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Langerhans cells (LC) are the principal dendritic cell (DC) population in the epidermis of the skin. Owing to their prominent position at the environmental barrier, LC have long been considered to be prototypic sentinel DC. More recently, the precise role of LC in the initiation and control of cutaneous immune responses has become debatable. To elucidate their contribution to immune regulation in the skin, our laboratories have generated genetically modified mice in which LC can be followed in situ by expression of enhanced green fluorescent protein and can be either inducibly or constitutively depleted in vivo. This review highlights the similarities and differences between these mouse models, discusses the discovery and functional significance of Langerin 1 dermal DC, and examines some recent data that help to shed light on LC function. The Langerhans cell paradigmLangerhans cells (LC) were discovered by Paul Langerhans in 1868 [1], but it took more than 100 years before they were first associated with the immune system and recognized as antigenpresenting cells [2]. In particular, Ralph Steinman's group [3] dissected the functional characteristics of LC starting from the seminal finding that murine epidermal LC mature into potent immunostimulatory dendritic cells (DC) in vitro. The work that followed shaped the concept of DC as professional inducers of T-cell immune responses largely by studying LC, though the term 'LC paradigm' was coined much later by Wilson and Villadangos [4].This concept assigned three key functions to LC/DC (reviewed in [5]). First, immature LC that reside in the periphery in the steady state are highly specialized in antigen uptake. LC form a dense network in the epidermis where they constantly scan the environment by extending and retracting their dendrites and are ideally positioned to detect any pathogen breaching the skin barrier [6]. Second, LC transport antigen to skindraining lymph nodes (LN), which is essential to ensure interaction with rare antigen-specific naive T cells. Stimulation by a number of pathogen products in addition to pro-inflammatory cytokines induces LC activation [7][8][9]. Activated LC downregulate expression of E-cadherin, which is thought to maintain their position in the epidermis, and begin to express CC Correspondence: Daniel Kaplan e-mail: DanKaplan@umn.edu Eur. J. Immunol. 2008. 38: 2369-2376 DOI 10.1002 HIGHLIGHTS 2369 Mini-Reviewwww.eji-journal.eu chemokine receptor 7, which guides the cells to the T-cell areas in the LN. Third, during migration the LC undergo a process of maturation in which they process antigen acquired in the skin and present it in the context of MHC class I/II. In addition, they dramatically upregulate their surface expression of co-stimulatory molecules and start to produce cytokines required for proper Th1 or Th2 instruction. Thus, by the time LC arrive in the LN, they have acquired the surface phenotype of a 'functionally' mature DC capable of activating naive T cells and thereby initiating an adaptive immune response specif...

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“…Clearly, systemic activation of DC will limit the capacity of DC to process any exogenous antigen in the MHC I or MHC II pathways, but may still allow presentation of endogenous antigens on MHC I. In this case, viral vectors that can prime CD8 1 T cells via direct infection of DC, such as recently described for lentiviruses [18], may offer viable approaches to vaccination. Alternatively, approaches that improve the regeneration of new immature DC, such as Flt3 ligand treatment [19], encapsulated in the vaccine may be beneficial.…”

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confidence: 99%

Blood‐stage Plasmodium berghei infection leads to short‐lived parasite‐associated antigen presentation by dendritic cells

et al. 2010

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Despite extensive evidence that Plasmodium species are capable of stimulating the immune system, the association of malaria with a higher incidence of other infectious diseases and reduced responses to vaccination against unrelated pathogens suggests the existence of immune suppression. Recently, we provided evidence that blood-stage Plasmodium berghei infection leads to suppression of MHC class I-restricted immunity to third party (non-malarial) antigens as a consequence of systemic DC activation. This earlier study did not, however, determine whether reactivity was also impaired to MHC class II-restricted third party antigens or to Plasmodium antigens themselves. Here, we show that while P. berghei-expressed antigens were presented early in infection, there was a rapid decline in presentation within 4 days, paralleling impairment in MHC class I-and II-restricted presentation of third party antigens. This provides important evidence that P. berghei not only causes immunosuppression to subsequently encountered third party antigens, but also rapidly limits the capacity to generate effective parasite-specific immunity.Key words: Antigen presentation . DC . Parasitic-Protozoan . Rodent . T cells IntroductionDespite extensive evidence that Plasmodium species are capable of stimulating the immune system, numerous studies have described immune suppression associated with infection, suggesting that Plasmodium parasites subvert immunity to promote persistence [1][2][3][4][5]. Various mechanisms have been suggested to underlie such suppression, including induction of CD4 1 T-cell apoptosis [6][7][8], suppression of DC function [9][10][11][12], or the generation of suppressive cytokines [1]. The observed humoral and cell-mediated immunity to malaria is, however, hard to reconcile with evidence of immune suppression, but may be explained by the ability of suppressive mechanisms to reduce but not completely prevent induction of immunity.Recently, we provided evidence that blood-stage Plasmodium berghei infection leads to suppression of MHC class I (MHC I)-restricted immune responses as a consequence of apparently normal DC activation [13]. While DC in infected mice were 1674shown to be fully competent in their ability to cross-present cellular antigens to CD8 1 T cells, provided they expressed antigen-MHC complexes on the surface, their activation phenotype led to a failure to capture newly encountered antigenic material and thus a failure to present such antigens [13]. In this case, DC were not directly suppressed but merely followed their normal maturation pathway after encounter with activatory stimuli. The net effect, however, was one of rapid, generalised immunosuppression because as the systemic infection progressed, all DC became activated, leaving no immature DC to capture subsequently encountered antigens.While systemic DC activation by P. berghei explained the reduced reactivity to subsequently encountered third party (nonmalarial) MHC I-restricted antigens, this earlier study did not determine whether reactivity...

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Skin-Derived Dendritic Cells Induce Potent CD8+ T Cell Immunity in Recombinant Lentivector-Mediated Genetic Immunization

Cited by 170 publications

References 65 publications

Langerhans cells and viral immunity

Langerhans cells and viral immunity

Insights into Langerhans cell function from Langerhans cell ablation models

Blood‐stage Plasmodium berghei infection leads to short‐lived parasite‐associated antigen presentation by dendritic cells

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