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. 1998 Dec;66(12):5867-75.
doi: 10.1128/IAI.66.12.5867-5875.1998.

Role of NK cells in early host response to chlamydial genital infection

C T Tseng  1 , R G Rank
Affiliations

Role of NK cells in early host response to chlamydial genital infection

C T Tseng et al. Infect Immun. 1998 Dec.

Abstract

The cell-mediated immune response has been documented to be the major protective immune mechanism in mice infected genitally with the agent of mouse pneumonitis (MoPn), a biovar of Chlamydia trachomatis. Moreover, there is strong evidence to indicate that gamma interferon (IFN-gamma) is a major effector mechanism of the cell-mediated immune response. Previous studies from this laboratory have also reported that the dominant cell population in the genital tract is the CD4 Th1 population. When experiments were performed by the enzyme-linked immunospot assay, high numbers of cells producing IFN-gamma were found in the genital tract, concomitant with resolution of the infection; however, in addition, an increase in IFN-gamma-producing cells which were CD4(-) was seen early in the infection. Since natural killer (NK) cells produce IFN-gamma and have been found to participate in the early responses in other infections, we hypothesized that NK cells are responsible for early IFN-gamma production in the murine chlamydial model. NK cells were quantified by the standard YAC-1 cytotoxicity assay and were found to appear in the genital tract as early as 12 h after intravaginal infection with MoPn. The cells were confirmed to be NK cells by abrogation of YAC-1 cell cytotoxicity by treatment in vitro and in vivo with anti-asialo-GM1. The early IFN-gamma response could also be depleted by treatment with anti-asialo-GM1, indicating that NK cells were responsible for the production of this cytokine. Of interest was our observation that depletion of NK cells also exacerbated the course of infection in the mice and elicited a Th2 response, as indicated by a marked increase in immunoglobulin G1 antibody. Thus, these data demonstrate that NK cells are not only responsible for the production of IFN-gamma early in the course of chlamydial genital tract infection but are also, via IFN-gamma, a significant factor in the development of the Th1 CD4 response and in the control of the infection.

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Figures

FIG. 1
FIG. 1
Kinetics of early cytokine expression in the genital tracts of mice intravaginally infected with MoPn. Total RNAs were extracted from genital tracts of five BALB/c mice at various times after MoPn genital infection. The RT-PCR was used to amplify specific signals of various cytokines and G3PDH (housekeeping gene) with specific primers. The resulting PCR products were resolved after electrophoresis onto a 2% agarose gel. For all the samples except IL-12 p40, lanes 1 to 7, specific signals at 0, 6, 12, 18, 24, 36, and 48 h after infection, respectively; lane 8, concanavalin A-stimulated splenocyte control; lane 9, positive plasmid control; lane 10, negative control; lane 11, empty. For IL-12 p40, lanes 1 to 7, signals at 0, 6, 12, 18, 24, 36, and 48 h after infection, respectively; lane 8, concanavalin A-stimulated control; lane 9, negative control; lanes 10 and 11, positive sample controls.
FIG. 2
FIG. 2
Kinetics of NK cell activity in mice intravaginally infected with MoPn. The NK cell activity in the MNCs derived from spleens, MLNs, ILNs, and genital tracts of infected mice were evaluated in vitro by a standard 4-h chromium assay, using 51Cr-labeled NK-sensitive YAC-1 cells as target cells, at an E/T ratio of 50 to 1. The spontaneous release of the labeled YAC-1 cells never exceeded 10% and was usually 6 to 7%. Each point indicates the mean of triplicate samples ± standard deviation.
FIG. 3
FIG. 3
Elimination of NK cell cytotoxicity for YAC-1 cells in the ILN and genital tract by in vitro treatment with anti-asialo-GM1 but not anti-CD3. Cell suspensions containing NK cells were collected 4 days after genital infection with MoPn.
FIG. 4
FIG. 4
Elimination of NK cell cytotoxicity for YAC-1 cells in the ILN and genital tract (GT) by in vivo treatment of mice with anti-asialo-GM1. Cell suspensions containing NK cells were collected 4 days after genital infection with MoPn.
FIG. 5
FIG. 5
Reduction in the number of IFN-γ-producing cells by two treatments as determined by the ELISPOT assay. (A) In vitro treatment of cells from the ILN with anti-asialo-GM1 and complement; (B) in vivo treatment of mice with anti-asialo-GM1. Cells were harvested from the ILN 4 days after infection with MoPn and assessed for IFN-γ-producing cells by the ELISPOT assay.
FIG. 6
FIG. 6
In vivo treatment of mice with anti-asialo-GM1 antibody resulted in a significant reduction in IFN-γ-specific transcripts in the genital tracts of mice intravaginally infected with MoPn. Total RNA was extracted from the genital tracts of mice treated with anti-asialo-GM1 or of untreated mice 36 h after chlamydial infection. RT-PCR was used to amplify signals for IFN-γ and G3PDH (housekeeping gene) by using specific primers. The resulting PCR products were electrophoresed on an agarose gel. Lanes 1 and 2, G3PDH-specific bands of mice with NK cells and NK-depleted mice, respectively; lanes 3 and 4 IFN-γ-specific PCR product for mice with NK cells and NK-depleted mice, respectively; lane M, molecular size markers.
FIG. 7
FIG. 7
Course of infection in mice depleted of NK cells by treatment with anti-asialo-GM1. Each point represents the percentage of 10 mice (two separate experiments of 5 mice each) positive for chlamydiae in the genital tract as determined by isolation in tissue culture. The infection was significantly prolonged in NK-depleted mice.
FIG. 8
FIG. 8
Titers of serum IgG1 and IgG2a antibodies to MoPn in mice depleted of NK cells by treatment with anti-asialo-GM1 30 days after intravaginal infection with MoPn. A significant increase in IgG1 was observed in NK-depleted mice.
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