Abstract
Infection of susceptible cells by herpes simplex virus (HSV) requires the interaction of the HSV gD glycoprotein with one of two principal entry receptors, herpes virus entry mediator (HVEM) or nectins. HVEM naturally functions in immune signaling, and the gD-HVEM interaction alters innate signaling early after mucosal infection. We investigated whether the gD-HVEM interaction during priming changes lymphocyte recall responses in the murine intravaginal model. Mice were primed with attenuated HSV-2 expressing wild-type gD or mutant gD unable to engage HVEM and challenged 32 days later with virulent HSV-2 expressing wild-type gD. HSV-specific CD8+ T cells were decreased at the genital mucosa during the recall response after priming with virus unable to engage HVEM but did not differ in draining lymph nodes. CD4+ T cells, which are critical for entry of HSV-specific CD8+ T cells into mucosa in acute infection, did not differ between the two groups in either tissue. An inverse association between Foxp3+ CD4+ regulatory T cells and CD8+ infiltration into the mucosa was not statistically significant. CXCR3 surface expression was not significantly different among different lymphocyte subsets. We conclude that engagement of HVEM during the acute phase of HSV infection influences the antiviral CD8+ recall response by an unexplained mechanism.
Highlights
Herpes simplex virus type 2 (HSV-2) is a common cause of infection, with 17% of American adults seropositive [1]
We investigated whether the gD-herpes virus entry mediator (HVEM) interaction during priming changes lymphocyte recall responses in the murine intravaginal model
herpes simplex virus (HSV) gD binds to three general classes of surface receptors, including herpesvirus entry mediator (HVEM), nectin-1 and -2, and specific sites in heparan sulfate [3]
Summary
Herpes simplex virus type 2 (HSV-2) is a common cause of infection, with 17% of American adults seropositive [1]. The immunologic effects of gD binding to HVEM during HSV infection have not been elucidated in detail, and our prior work in a murine intravaginal challenge model identified differences in chemokine responses at the mucosa depending on whether virus could engage HVEM, acute cellular responses were not appreciably affected [9]. HVEM is not expressed on T cells of mice that lack Foxp3 [17], a transcription factor which defines the major Treg subset [18] Together, these observations suggest an important role for HVEM in the generation and function of effector memory lymphocytes and in the function of Tregs. We observe differences in the HSV-specific CD8+ T-cell recall response at the genital mucosa based on the gD-HVEM interaction during priming. Clinical symptoms were generally not observed after either inoculation, though sporadically individual mice primed with attenuated viruses had perivaginal hair loss or mild lesions which resolved prior to challenge
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