Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

Harandi, Ali M.; Svennerholm, Bo; Holmgren, Jan; Eriksson, Kristina

doi:10.1099/0022-1317-82-4-845

Cited by 122 publications

(129 citation statements)

References 41 publications

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“…However, IFN-␥ responses in the lymphoid organs appeared to be dominant. We and others have previously documented the critical importance of IFN-␥ response for immune protection against genital herpes infection in mice (23)(24)(25)(26). Furthermore, we could show that mice immunized with gD plus ␣-GalCer had high levels of gD-specific IgG Abs in their sera and vaginal extracts.…”

Section: Discussionsupporting

confidence: 54%

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

Lindqvist

Persson

Thörn

et al. 2009

The Journal of Immunology

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Development of mucosal adjuvants to generate immunity in the female genital tract may have important implications for the development of vaccines to counter sexually transmitted infections. α-Galactosylceramide (α-GalCer) is presented by CD1d molecule on APCs to invariant Vα14+ NKT (iNKT) cells, which upon activation rapidly produce large amounts of immunomodulatory cytokines, leading to activation of a variety of innate and adaptive immune cells. Here, we assessed whether α-GalCer could act as a mucosal adjuvant for induction of protective immunity against genital herpes. We found that intranasal immunization with HSV-2 glycoprotein D (gD) in combination with α-GalCer elicits strong systemic gD-specific IgG Ab response as well as lymphoproliferative response with a mixed Th1/Th2 cytokine profile in the spleen, mediastinal lymph nodes, and genital lymph nodes. Importantly, such an immunization scheme conferred complete protection against an otherwise lethal vaginal HSV-2 challenge. We could also show that intravaginal immunization with gD plus α-GalCer generates potent gD-specific lymphoproliferative and IFN-γ responses in the genital lymph nodes and spleen. Furthermore, the vaginally immunized mice developed a strong systemic and mucosal IgG Ab response and protection against vaginal HSV-2 challenge. The mucosal adjuvant effect of α-GalCer was found to be mediated via CD1d molecule and appeared to be independent of the usage of the adaptor molecule MyD88. To our knowledge, this is the first report on the mucosal adjuvant effect of α-GalCer for induction of protective immunity against a sexually transmitted pathogen.

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Section: Discussionsupporting

confidence: 54%

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

Lindqvist

Persson

Thörn

et al. 2009

The Journal of Immunology

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“…In the absence of T-bet, CD8+ T cells may produce higher amounts of the cytokine, since T-bet is not able to inhibit IL-2 production, which may, at least to some extent, be the case in wild-type cells. Moreover, the role of CD8+ T cells may be of minor importance during HSV-2 infection, since mice depleted of CD8+ T cells are still able to clear the infection after vaccination (Harandi et al, 2001), which may also explain the loss of function of T-bet in HSV-2-specific CD8+ T cells. In contrast to HSV-2 infection, T-bet is necessary for the antigen-driven development of CD8+ T cells into effector cells, and for a sufficient cytotoxic response together with optimal IFN-γ production in response to lymphocytic choriomeningitis virus (Sullivan et al, 2003).…”

Section: Cd8+ T Cellsmentioning

confidence: 99%

Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection

Svensson

Bellner

Magnusson

et al. 2007

Journal of Reproductive Immunology

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Genital herpes, caused by herpes simplex virus type 2 (HSV-2), is the most common genital ulcer disease worldwide. HSV-2 infection causes a variety of symptoms, ranging from subclinical/silent infection to severe and recurrent episodes of genital blisters and ulcers, and the virus can also in rare cases cause meningitis. In primary infection, the virus sequentially enters and replicates in epithelial cells followed by local sensory neurons. In the latter, a life-long infection is established via the induction of viral latency or dormancy. Latent virus is however continuously reactivated, also in those with a silent infection, which results in a low-grade viral replication and shedding into the vaginal lumen. This reactivation can in many individuals be amplified following e.g. stress, hormonal variations or immune suppression, which results in recurrent genital disease.

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“…Hence, antibody-mediated immunity is insufficient for protection against, e.g., Chlamydia trachomatis or herpes simplex virus 2 infections [1][2][3]. Rather, these infections can only be prevented by robust Ag-specific CD4 1 T cells in the genital tract, as documented in several of the animal models of these infections [2,4,5]. Previous studies have shown that i.n.…”

Section: Introductionmentioning

confidence: 99%

CD4⁺ T‐cell immunity in the female genital tract is critically dependent on local mucosal immunization

et al. 2011

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Immunizations via the i.n. and intravaginal (ivag) routes effectively generate strong genital tract antibody-mediated immunity. To what extent the same is true for T-cell responses is incompletely known. Therefore, we set out to investigate optimal conditions for stimulation of genital tract CD41 T-cell responses, using adoptive transfer of mouse DO11.10 TCR transgenic T cells specific for OVA and OVA conjugated to cholera toxin (CT) as an immunogen. We observed that progesterone was required for a T-cell response following ivag immunization, whereas estradiol prevented a response. Although i.n. immunization stimulated OVA-specific CD4 1 T-cell responses in the draining LNs, it was substantially less effective compared to ivag. More importantly, an ivag booster immunization was absolutely required to attract T cells to the genital tract mucosa itself. While clinical use of CT is precluded because of its toxicity, we developed a combined adjuvant vector based on a non-toxic derivative of CT and immune-stimulating complexes. The CTA1-DD/immunestimulating complexes (ISCOMs) adjuvant together with major outer membrane protein was effective at stimulating genital tract CD4 1 T-cell immunity and protection against a live chlamydial infection, which holds promise for the development of mucosal vaccines against sexually transmitted infections.

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Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

Abstract: The role of B, CD4 M T and CD8 M T cells in both primary genital infection with attenuated herpes simplex virus type 2 (HSV-2) and development of protective immunity to a later challenge with virulent HSV-2 using lymphocyte-deficient mice has been elucidated.

Cited by 122 publications

References 41 publications

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection

CD4⁺ T‐cell immunity in the female genital tract is critically dependent on local mucosal immunization

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Differential roles of B cells and IFN-γ-secreting CD4+ T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice

Abstract: The role of B, CD4 M T and CD8 M T cells in both primary genital infection with attenuated herpes simplex virus type 2 (HSV-2) and development of protective immunity to a later challenge with virulent HSV-2 using lymphocyte-deficient mice has been elucidated.

Cited by 122 publications

References 41 publications

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection

CD4+ T‐cell immunity in the female genital tract is critically dependent on local mucosal immunization

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CD4⁺ T‐cell immunity in the female genital tract is critically dependent on local mucosal immunization