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Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection.

ABSTRACT: In many infections, especially those that are chronic such as Herpes Simplex Virus-1 (HSV-1), the outcome may be influenced by the activity of one or more types of regulatory T cells (Tregs). Some infections can cause Treg expansion, but how viruses might promote preferential Treg expansion is has been unclear. In this report, we demonstrate a possible mechanism by which HSV (Herpes Simplex virus-1) infection could act to signal and expands the Treg population. We show that CD4(+) FoxP3(+) Tregs up- regulate HVEM (herpes virus entry mediator), which is a binding site for major viral glycoprotein HSVgD, following HSV infection, which is a binding site for major viral glycoprotein HSVgD. Recombinant HSVgD enhanced the proliferation of CD4(+) FoxP3(+) Tregs cells in-vitro. Furthermore, compared to wild type (WT), HVEM deficient mice (HVEM-/-) generated a weaker Treg responses represented by significantly diminished ratios of CD4(+)FoxP3(+)/CD4(+)FoxP3(-) cells along with diminished proportions of FoxP3(+) Tregscells co-expressing Treg activation markers and a reduced MFI of FoxP3 expression on CD4(+) T cells. Consistent with defective Treg responses, HVEM-/- animals were more susceptible to HSV-1 induced ocular immunopathology, with more severe lesions in HVEM-/- animals. Our results indicate that HVEM regulates Treg responses, and its modulation could represent a useful approach to control HSV induced corneal immunopathology.

SUBMITTER: Sharma S

PROVIDER: S-EPMC4150749 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection.

Sharma Shalini S Rajasagi Naveen K NK Veiga-Parga Tamara T Rouse Barry T BT

Microbes and infection 20140621 8

In many infections, especially those that are chronic such as Herpes Simplex Virus-1 (HSV-1), the outcome may be influenced by the activity of one or more types of regulatory T cells (Tregs). Some infections can cause Treg expansion, but how viruses might promote preferential Treg expansion is has been unclear. In this report, we demonstrate a possible mechanism by which HSV (Herpes Simplex virus-1) infection could act to signal and expands the Treg population. We show that CD4(+) FoxP3(+) Tregs ...[more]

PMID: 24956596

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Project description:UNLABELLED:Ocular herpes simplex virus 1 (HSV-1) infection leads to a potentially blinding immunoinflammatory syndrome, herpes stromal keratitis (HSK). Herpesvirus entry mediator (HVEM), a widely expressed tumor necrosis factor (TNF) receptor superfamily member with diverse roles in immune signaling, facilitates viral entry through interactions with viral glycoprotein D (gD) and is important for HSV-1 pathogenesis. We subjected mice to corneal infection with an HSV-1 mutant in which HVEM-mediated entry was specifically abolished and found that the HVEM-entry mutant produced clinical disease comparable to that produced by the control virus. HVEM-mediated induction of corneal cytokines, which correlated with an HVEM-dependent increase in levels of corneal immune cell infiltrates, was also gD independent. Given the complexity of HVEM immune signaling, we used hematopoietic chimeric mice to determine which HVEM-expressing cells mediate HSV-1 pathogenesis in the eye. Regardless of whether the donor was a wild-type (WT) or HVEM knockout (KO) strain, HVEM KO recipients were protected from ocular HSV-1, suggesting that HVEM on radiation-resistant cell types, likely resident cells of the cornea, confers wild-type-like susceptibility to disease. Together, these data indicate that HVEM contributes to ocular pathogenesis independently of entry and point to an immunomodulatory role for this protein specifically on radiation-resistant cells. IMPORTANCE:Immune privilege is maintained in the eye in order to protect specialized ocular tissues, such as the translucent cornea, from vision-reducing damage. Ocular herpes simplex virus 1 (HSV-1) infection can disrupt this immune privilege, provoking a host response that ultimately brings about the majority of the damage seen with the immunoinflammatory syndrome herpes stromal keratitis (HSK). Our previous work has shown that HVEM, a host TNF receptor superfamily member that also serves as a viral entry receptor, is a critical component contributing to ocular HSV-1 pathogenesis, although its precise role in this process remains unclear. We hypothesized that HVEM promotes an inflammatory microenvironment in the eye through immunomodulatory actions, enhancing disease after ocular inoculation of HSV-1. Investigating the mechanisms responsible for orchestrating this aberrant immune response shed light on the initiation and maintenance of HSK, one of the leading causes of infectious blindness in the developed world.

Dataset Information

Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection.

Publications

Herpes virus entry mediator (HVEM) modulates proliferation and activation of regulatory T cells following HSV-1 infection.

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