Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis

Kittan, Nicolai A.; Bergua, Antonio; Haupt, Sabrina; Donhauser, Norbert; Schuster, Philipp; Korn, Klaus; Harrer, Thomas; Schmidt, Bárbara

doi:10.4049/jimmunol.179.6.4219

Cited by 36 publications

(34 citation statements)

References 52 publications

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“…However, the HSV genes involved in downregulating DC functions are unknown. As LAT is the only HSV-1 gene abundantly transcribed during latency, it is a candidate for modulating DC Ag-presenting function during latent infection (33)(34)(35). We hypothesize that LAT inhibits phenotypic maturation of DCs, and subsequently impairs their function of stimulating TG-resident CD8 + T cells.…”

Section: Introductionmentioning

confidence: 94%

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

et al. 2012

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We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8+ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected. Some CD8 + T cells are adjacent to DCs, suggesting possible interactions. It has previously been shown that wild-type HSV-1 interferes with DC maturation. Here we show for the first time that this is associated with LAT expression, since compared to LAT ( -) virus: (1) LAT ( + ) virus interfered with expression of MHC class I and the co-stimulatory molecules CD80 and CD86 on the surface of DCs; (2) LAT ( + ) virus impaired DC production of the proinflammatory cytokines IL-6, IL-12, and TNF-a; and (3) DCs infected in vitro with LAT ( + ) virus had significantly reduced the ability to stimulate HSV-specific CD8 + T cells. While a similar number of DCs was found in LAT ( + ) and LAT ( -) latently-infected TG of CD11c/eYFP transgenic mice, more HSV-1 Ag-positive DCs and more exhausted CD8 T cells were seen with LAT ( + ) virus. Consistent with these findings, HSV-specific cytotoxic CD8 + T cells in the TG of mice latently-infected with LAT ( + ) virus produced less IFN-c and TNF-a than those from TG of LAT ( -) infected mice. Together, these results suggest a novel immune-evasion mechanism whereby the HSV-1 LAT increases the number of HSV-1 Ag-positive DCs in latently-infected TG, and interferes with DC phenotypic and functional maturation. The effect of LAT on TG-resident DCs may contribute to the reduced function of HSVspecific CD8 + T cells in the TG of mice latently infected with LAT ( + ) virus.

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Section: Introductionmentioning

confidence: 94%

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

et al. 2012

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“…Following KSHV infection of pDCs, we also observed upregulation of the costimulatory molecules CD83 and CD86. These have been shown to be activated by other herpesviruses, including HSV-1 and HCMV (19,32). Intriguingly, one of the downstream effects of CD86 activation is the binding of CTLA-4, which can modulate host T-cell responses (22).…”

Section: Discussionmentioning

confidence: 99%

Activation of Plasmacytoid Dendritic Cells by Kaposi's Sarcoma-Associated Herpesvirus

West

Gregory

Sivaraman

et al. 2011

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with multiple human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Following primary infection, KSHV typically goes through a brief period of lytic replication prior to the establishment of latency. Plasmacytoid dendritic cells (pDCs) are the major producers of type 1 interferon (IFN), primarily in response to virus infection. Toll-like receptors (TLRs) are key components of the innate immune system, and they serve as pathogen recognition receptors that stimulate the host antiviral response. pDCs express exclusively TLR7 and TLR9, and it is through these TLRs that the type 1 interferon response is activated in pDCs. Currently, it is not known whether KSHV is recognized by pDCs and whether activation of pDCs occurs in response to KSHV infection. We now report evidence that KSHV can infect human pDCs and that pDCs are activated upon KSHV infection, as measured by upregulation of CD83 and CD86 and by IFN-␣ secretion. We further show that induction of IFN-␣ occurs through activation of TLR9 signaling and that a TLR9 inhibitor diminishes the production and secretion of IFN-␣ by KSHV-infected pDCs.

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“…HIV coinfection is associated with low pDC numbers and poor pDC responses to HSV (1). Decreased circulating pDC numbers and HSV responsiveness were seen in rare persons with HSV-1 retinitis (27). Furthermore, pDC activation is amenable to pharmacologic manipulation by synthetic agonist compounds (37).…”

mentioning

confidence: 99%

Peripheral Blood CD4 T-Cell and Plasmacytoid Dendritic Cell (pDC) Reactivity to Herpes Simplex Virus 2 and pDC Number Do Not Correlate with the Clinical or Virologic Severity of Recurrent Genital Herpes

Moss

Magaret

Laing

et al. 2012

J Virol

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Leukocytes participate in the immune control of herpes simplex virus (HSV). Data from HIV coinfections, germ line mutations, and case reports suggest involvement of CD4 T cells and plasmacytoid dendritic cells (pDC). We investigated the relationships between these cells and recurrent genital herpes disease severity in the general population. Circulating CD4 T-cell responses to HSV-2 were measured in specimens from 67 immunocompetent individuals with measured genital lesion and HSV shedding rates. Similarly, pDC number and functional responses to HSV-2 were analyzed in 40 persons. CD4 responses and pDC concentrations and responses ranged as much as 100-fold between persons while displaying moderate within-person consistency over time. No correlations were observed between these immune response parameters and genital HSV-2 severity. Cytomegalovirus (CMV) coinfection was not correlated with differences in HSV-2-specific CD4 T-cell responses. The CD4 T-cell response to HSV-2 was much more polyfunctional than was the response to CMV. These data suggest that other immune cell subsets with alternate phenotypes or anatomical locations may be responsible for genital herpes control in chronically infected individuals.

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Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis

Cited by 36 publications

References 52 publications

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

The Herpes Simplex Virus Type 1 Latency-Associated Transcript Inhibits Phenotypic and Functional Maturation of Dendritic Cells

Activation of Plasmacytoid Dendritic Cells by Kaposi's Sarcoma-Associated Herpesvirus

Peripheral Blood CD4 T-Cell and Plasmacytoid Dendritic Cell (pDC) Reactivity to Herpes Simplex Virus 2 and pDC Number Do Not Correlate with the Clinical or Virologic Severity of Recurrent Genital Herpes

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