Monophosphoryl lipid A and QS21 increase CD8 T lymphocyte cytotoxicity to herpes simplex virus-2 infected cell proteins 4 and 27 through IFN-gamma and IL-12 production

We have shown previously that IFN-gamma pretreatment of human epidermal cel ls (ECs) cultured in vitro partially reverses downregulation of surface MHC class I by HSV infection, allowing recognition by CD8 CTLs, and that HSV i mmediate early (IE)/early (E) proteins are the predominant targets for CD8 CTLs, In this study of 25 subjects, CD8 CTLs recognized the HSV-2 IE infect ed cell protein 27 (ICP27) (expressed in autologous IFN-gamma-pretreated, V accinia virus recombinant-infected ECs) in all subjects studied, ICP4 in 89 %, and ICP0 in 11%, The main hierarchy of recognition was ICP27 > ICP4, ICP 27 was the dominant target in 89% of subjects but showed great individual v ariability in the degree of cytotoxicity. CD8 cytotoxicity specific for HSV -2 IE proteins was enhanced by 48-67% when CD8 CTLs were coincubated with t he combination of monophosphoryl lipid A and QS21 adjuvants at the time of Ag presentation. These adjuvants also significantly enhanced IL-12 and IFN- gamma production from nonadherent mononuclear cells stimulated by HSV-2-inf ected ECs, Addition of IL-12 and IFN-gamma at the time of initial Ag presen tation enhanced CD8 cytotoxicity to levels comparable with those stimulated by the adjuvants, Addition of neutralizing Abs to IL-12 or IFN-gamma inhib ited CD8 T cell cytotoxicity up to 95% when a combination of the Abs were a dded at the time of initial Ag presentation. Therefore, the mechanism for t he enhancement of CD8 T cell cytotoxicity by adjuvants in this system appea rs to be via increased levels of IL-12 and IFN-gamma.