Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Abstract

NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.

IL-21–Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor–Dependent Manner

“…In addition, they also have shown that NK cells alone can present Ags to CD4 T cells in the context of HSV infection after TLR activation. They suggested that this interaction could occur in herpetic lesions and also in draining lymph nodes (38). These observations support the hypothesis that cytokines, such as IL-21, involved in chronic inflammation or infections, could account for HLA-DR + NK cell differentiation (20).…”

“…The molecular mechanism and physiopathological context regulating MHC-II expression and Ag presentation functions in human NK cells were never clearly investigated. In this context, Kim and colleagues (38) confirmed that activated NK cells express increased levels of MHC-II. In addition, they also have shown that NK cells alone can present Ags to CD4 T cells in the context of HSV infection after TLR activation.…”

“…The regulation of MHC-II expression following exposition to inflammatory stimuli depends on the CIITA (36). However, although it was previously acknowledged that NK cell clones could process and present some soluble Ags such as tetanus toxoid (37), the expression of HLA-DR on NK cells was mostly considered as an activation marker (38)(39)(40)(41)(42). As previously suggested by Evans et al (42), the identification of HLA-DR + NK cells after culture with IL-2 might result from the expansion of rare HLA-DR + cells initially present in peripheral blood NK cells.…”

“…Moreover, this phenomenon seems to be tightly regulated in a STAT3-dependent manner. Accordingly, IL-21 might represent a regulatory mechanism tuning CD4 and NK lymphocyte interactions during inflammation or chronic infections, as suggested by the identification of HLA-DR + NK cells during HSV infection (38).…”

NK cells require IL-28R for optimal in vivo activity

“…However, the TLR-induced anti-HSV2 response was abolished in IL-28R −/− mice, similar to that observed in IFNAR1 −/− (interferon alpha/beta receptor 1) mice (21). Although HSV2 antigens were recently shown to directly activate NK cells (22), the role of NK cells was not addressed using the IL-28R −/− mice. Furthermore, these mice have not been used to explore the role of IL-28R in NK cell-mediated control of tumors, nor has the relationship of host IL-28R and IFNAR1 been Significance Natural killer (NK) cells are naturally circulating innate lymphocytes that sense altered cells, including pathogen-activated and early-transformed cells.…”