| As with many current vaccines, strategies against HSV-2 have been largely directed at generating potent antibody responses, but thus far have been unsuccessful at preventing HSV infection. Herpes-specific CD8+ T cell responses are critical for viral resolution and limiting spread, therefore vaccine-mediated protection will likely require viral-specific memory CD8+ T lymphocytes at mucosal sites to block infection of neuronal tissue. To identify critical characteristics of CD8+ T cells following an effective HSV-2 immunization, CD8+ T cells from normal B6 mice or mice deficient in IFN-γ or the IFN-γ receptor were activated in vitro in the presence of IFN-γ or IL-4 to generate a series of effector populations (Tc1 and Tc2-like, respectively) that secreted different levels of IFN-γ and expressed different levels of HSVspecific cytolytic function. Compared to Tc1 cells, Tc2-like cells produced the type 2 cytokines IL-4 and IL-5, exhibited decreased IFN-γ secretion, and diminished proliferation in vitro. Clearance of HSV-2 by adoptively transferred Tc2-like cells was delayed relative to Tc1 cell recipients and delayed clearance correlated with reduced IFN-γ secretion and HSV-specific CTL activity, rather than decreased proliferation or impaired homing in vivo. Together these results suggest that high-level expression of protective effector T cell functions is necessary for optimal clearance of HSV-2 from the genital epithelium. To determine how adjuvants affect the elicited CD8+ T cell response, adjuvant stimuli (CpG, MPL and Poly(I:C)) were examined for their ability to induce critical signals in BMDC necessary for appropriate development of CD8+ memory T cells. Mice vaccinated with MPL- or CpG-stimulated, peptide-pulsed BMDC exhibited increased CTL activity compared to those given Poly(I:C)-treated BMDC. Greater numbers of antigen-specific memory cells were detected in the spleen and iliac LN of the MPL-stimulated BMDC group. The results of these studies suggest that specific TLR ligand adjuvants may affect the quality of vaccine-elicited CD8+ T cells which may, in turn, impact vaccine-mediated protection. This research has contributed to understanding the significance of CD8+ memory T cells and homing patterns generated following immunization to optimize the immune response, ultimately aiding in identifying vaccine tactics that stimulate the memory response required for protection during HSV-2 challenge. |
