Herpes Simplex Virus Infects Skin γδ T Cells before Langerhans Cells and Impedes Migration of Infected Langerhans Cells by Inducing Apoptosis and Blocking E-Cadherin Downregulation

Puttur, Franz; Fernandez, Marian A.; White, R. W.; Roediger, Ben; Cunningham, Anthony L.; Weninger, Wolfgang; Jones, Cheryl

doi:10.4049/jimmunol.0904106

Cited by 52 publications

(73 citation statements)

References 53 publications

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“…Moreover, we show an inverse relationship between skin T RM and DETCs that is indicative of competition for persistence within an epidermal niche. It seems that DETCs either leave or die following HSV infection, the latter potentially the result of direct infection by this cytopathic virus (25). T RM populate this DETC-replete skin, as well as the epidermis that borders the site of infection where many DETCs remain.…”

Section: Discussionmentioning

confidence: 99%

Persistence of skin-resident memory T cells within an epidermal niche

Zaid

Mackay

Rahimpour

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

262

310

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Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (T RM ). In the skin, these memory CD8 + T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal T RM preferentially at the site of prior infection despite sustained migration. Computational simulation of T RM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of T RM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin T RM . Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche. T he skin is a complex organ that acts as a primary barrier between the body and the environment. Multiple leukocyte subsets reside within the main compartments of the skin, the dermis and the epidermis, as well as the hair follicles that are contiguous with the epidermis. Populations of macrophages, dendritic cells, mast cells, γδ T cells and αβ T cells are present in the dermis, and Langerhans cells (LCs) and dendritic epidermal γδ T cells (DETCs) lie in a strategic network in the epidermis (1). We recently described a population of memory CD8 + T cells that enter the epidermis and hair follicles during infection or inflammation and become long-lived populations of tissue-resident memory T cells (T RM ) (2-5). These memory T cells are sequestered in this site and are distinct from circulating effector memory (T EM ) and central memory (T CM ) populations (3, 6). Memory CD8 + T cells in the epidermis display a dendritic morphology and move at a slower velocity than T cells within the dermis. These memory T cells are sequestered in the skin epithelial layer and do not recirculate to other tissues. In contrast, memory CD4 + T cells are found within the dermis and at least a proportion of these cells are capable of recirculating around the body (3, 7).In this study, we sought to further examine the mechanisms of T RM persistence within the skin. We reveal that skin T RM persist at the site of their formation and despite displaying a sustained mode of random migration, the slow rate of this movement locally constrains these memory cells. Examination of other cells in this environment showed that although epidermal T RM regularly interact with LC, these interactions were not required for persistence. In contrast, skin tissue-resident memory T cells replaced DETCs in the epidermis, seem...

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Section: Discussionmentioning

confidence: 99%

Persistence of skin-resident memory T cells within an epidermal niche

Zaid

Mackay

Rahimpour

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

262

310

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“…Therefore, Langerhans cells (LCs) are likely to be involved in initial HSV Ag uptake (9), as shown by older murine studies (10). However, recent studies in mice demonstrated that migrating dermal CD103 + , langerin-expressing DCs are the major transporters of HSV Ag out of skin and, together with resident CD8 + DCs, are the major presenters of HSV Ag to CD8 T lymphocytes in lymph nodes (11,12), probably after Ag transfer from LCs (13). No human equivalent of the CD103 + dermal DC subset has been described, nor has a similar sequence of events, although it was shown that HSV-infected monocyte-derived DCs (MDDCs) undergo apoptosis and can be taken up by bystander uninfected MDDCs, which can then present HSV Ag to CD8 T lymphocytes (14).…”

mentioning

confidence: 99%

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

The Journal of Immunology

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NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.

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“…Langerhans cells (LCs) in the epidermis of the stratified squamous anogenital mucosa are a target cell for productive infection by both HSV-2 and HIV-1 (17)(18)(19)(20). They are major cell targets for HIV-1 in the uninflamed epidermis, despite constituting only 1-2% of epidermal cells, and they extend their processes superficially into its upper layers to form a cellular network in contact with each other.…”

mentioning

confidence: 99%

“…Apoptotic DCs are then taken up by bystanders and HSV-2 Ag presented to T cells (27). HSV-2 has also been shown to inhibit murine and human LC maturation, and induce apoptosis (17,20).…”

mentioning

confidence: 99%

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

Marsden

Donaghy

Bertram

et al. 2015

The Journal of Immunology

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Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2–infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1–DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-α was by far the most prominent cytokine in the supernatant and also within HSV-2–infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF-α (and low levels of IFN-β). Neutralizing Ab to TNF-α and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions.

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Herpes Simplex Virus Infects Skin γδ T Cells before Langerhans Cells and Impedes Migration of Infected Langerhans Cells by Inducing Apoptosis and Blocking E-Cadherin Downregulation

Cited by 52 publications

References 53 publications

Persistence of skin-resident memory T cells within an epidermal niche

Persistence of skin-resident memory T cells within an epidermal niche

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

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