Overexpression of Interleukin-15 Compromises CD4-Dependent Adaptive Immune Responses against Herpes Simplex Virus 2

Abstract

Interleukin-15 (IL-15) is necessary for the development and function of NK/NKT cells and the maintenance of naive and memory CD8؉ T cells. In the absence of IL-15, protective innate immunity is not available; however, a functional adaptive immune response against vaginal herpes simplex virus 2 (HSV-2) is generated. Mice overexpressing IL-15 (IL-15tg mice) have higher numbers of NK cells, greater NK-derived gamma interferon, and more CD8 ؉ T cells. Here we examined the consequences of IL-15 overexpression for innate and adaptive immunity against genital HSV-2. Surprisingly, IL-15tg mice immunized against HSV-2 were not protected against genital HSV-2 challenge compared to control immunized mice. IL-15tg mice had a higher frequency of NK cells in the genital mucosa than control mice. However, immunized IL-15tg mice had significantly lower numbers of HSV-2-specific CD4 ؉ T cells than B6 mice. We then confirmed that CD4 ؉ T cells, but not CD8 ؉ T cells, are essential for protection against intravaginal HSV-2 challenge. Since we observed less protection in immunized IL-15tg mice, we then examined if the adaptive immune responses generated in an environment with overexpression of IL-15 could provide protection against HSV-2 in an environment with normal levels of IL-15 expression. We adoptively transferred immunized cells from IL-15tg and B6 mice into naive RAG-1 ؊/؊ mice and found that the cells from immunized IL-15tg mice were able to provide protection in this IL-15-normal environment. Our data suggest that overexpression of IL-15 results in a reduced CD4 ؉ T cell-mediated adaptive immune response against genital HSV-2.

Novel Roles of Cytoplasmic ICP0: Proteasome-Independent Functions of the RING Finger Are Required To Block Interferon-Stimulated Gene Production but Not To Promote Viral Replication

“…Virus growth is mirrored by the observed pathology in these mice and further confirmed by measurement of levels of IFN-␥, a cytokine produced by NK cells that represents a characteristic feature of the innate immune response to replicating genital HSV (107)(108)(109). Consistent with our data, previous work in lymphocyte-deficient rag2 Ϫ/Ϫ mice demonstrated that an HSV-2 virus expressing an NLS mutant of ICP0 was lethal in 80% of mice compared to only 20% infected with a RING finger mutant (110).…”

The role of interleukin-15 in inflammation and immune responses to infection: implications for its therapeutic use

“…Surprisingly, despite IL-15 transgenic mice having higher numbers of NK cells in their genital mucosa and more CD8 + T lymphocytes than control mice, HSV-2 immunized IL-15 transgenic mice were susceptible to genital HSV-2 infection following HSV-2 challenge. This finding was attributed to a reduction in HSV-2-specific CD4 + T lymphocytes due to competition from the increased numbers of CD8 + lymphocytes produced by excess IL-15 for space and ligands [96]. Whereas similar susceptibility to genital HSV-2 infection was seen in another study with IL-15 transgenic mice, this result was attributed to aberrantly high levels of TGF-β1 and decreased levels of IFN-γ being produced by the intraepithelial cells of the uterus/vagina, in addition to impaired production of IFN-γ by T lymphocytes in these mice [97].…”

Innate and Adaptive Immune Responses to Herpes Simplex Virus

“…In another study, Vollstedt et al compared rag2 – / – mice (which are deficient in T and B cells) and rag2 – / – γ c – / – mice (which have an additional deficiency in NK cells) and found that NK cells are not required for resistance to HSV-1 [6]. Finally, mice overexpressing IL-15 were unable to survive HSV challenge, despite having higher numbers of NK cells and lower viral titers early in the infection [141]. …”