NKT Cells Determine Titer and Subtype Profile of Virus-Specific IgG Antibodies during Herpes Simplex Virus Infection

Abstract

Invariant NKT cells (iNKT cells) are innate lymphocytes that recognize lipid-derived Ags presented by the MHC class I–related protein CD1d. In this study, we analyzed the role of iNKT cells in the generation of Abs against HSV type 1 (HSV-1). In sera from healthy hman donors, we found a correlation between HSV-1–specific IgG titers and proportions of CD4+ iNKT cells. In HSV-1–infected iNKT cell–deficient mice, the amount of specific IgM and IgG Abs were significantly reduced compared with wild-type mice. Moreover, iNKT cell–deficient mice were unable to upregulate CD1d on B cells and failed to establish an IFN-γ–driven subtype profile of HSV-1–specific IgG Abs. In spleens of HSV-1–infected wild-type mice, the percentage of iNKT cells expressing CCR6, a marker for inflammatory iNKT cells secreting IFN-γ, was significantly decreased at 6 mo postinfection, suggesting that these cells were released from the spleen to other tissues. Finally, in vitro experiments showed that in the absence of CD1d-restricted cells, HSV-1 induced markedly lower IFN-γ production in splenocytes from naive mice. Taken together, our results indicate that iNKT cells shape the Ab response to HSV-1 infection and provide a basis for rational development of antiviral vaccines.

Viral Persistence Induces Antibody Inflation without Altering Antibody Avidity

“…Here, we found that virus-specific IgG2b and IgG2c antibodies also inflate during persistent MCMV infection, and that the degree of antibody inflation relates to the dose of the initial viral inoculum. In other persistent infections, such as chronic lymphocytic choriomeningitis virus (LCMV) (25,26) or herpes simplex virus infection (27), virus-specific antibodies also accumulate with time, albeit to various degrees. However, the serum levels of these virus-specific IgG antibodies eventually decline.…”

B Cell Help by CD1d-Rectricted NKT Cells

“…The amount of virus-specific IgM and IgG is significantly reduced in iNKT cell-deficient mice compared to their wild-type counterparts [74]. Furthermore, iNKT cells are relevant in shaping the IgG subtype profile of HSV-1-specific Abs, as IgG2c and IgG3 Abs are barely detectable in Jα18 −/− mice compared to WT animals [74]. This deficit results from insufficient IFNγ production that promotes the switch to IgG2c and IgG3, suggesting that iNKT cells are required for HSV-1-induced IFNγ production [74].…”

“…iNKT cell help to B cells may occur also in a spontaneous manner, that is to say in the absence of αGalCer, as it was demonstrated by investigating the role of iNKT cells in HSV-1-induced B cell responses [74]. The amount of virus-specific IgM and IgG is significantly reduced in iNKT cell-deficient mice compared to their wild-type counterparts [74].…”

“…The amount of virus-specific IgM and IgG is significantly reduced in iNKT cell-deficient mice compared to their wild-type counterparts [74]. Furthermore, iNKT cells are relevant in shaping the IgG subtype profile of HSV-1-specific Abs, as IgG2c and IgG3 Abs are barely detectable in Jα18 −/− mice compared to WT animals [74].…”

“…Furthermore, iNKT cells are relevant in shaping the IgG subtype profile of HSV-1-specific Abs, as IgG2c and IgG3 Abs are barely detectable in Jα18 −/− mice compared to WT animals [74]. This deficit results from insufficient IFNγ production that promotes the switch to IgG2c and IgG3, suggesting that iNKT cells are required for HSV-1-induced IFNγ production [74]. Another example of spontaneous iNKT cell help to B cells, which has relevant pathophysiological implications, occurs in a mouse model of primary biliary cirrhosis elicited by the infection of mice with the hepatotropic spingomonas N. aromaticivorans [75].…”