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Antiviral immune responses in the genital tract: clues for vaccines

Nature Reviews Immunology volume 10, pages 699–711 (2010)Cite this article

Subjects

Key Points

  • Sexually transmitted viruses (STVs) are a major cause of morbidity and mortality in humans worldwide. Yet, for the most part, vaccines that prevent transmission of STVs are not available.

  • Certain STVs, such as herpes simplex virus type 2 and human papillomavirus, cause much more severe disease in women than in men. One of the underlying reasons for this variation is the differences in the anatomy of the genital mucosa between females and males; the female genital tract has a much larger area for viral invasion and contains many more target cell types.

  • Innate immunity in the genital mucosa is provided by a physical barrier (such as mucus and epithelial cells), antimicrobial factors (such as antimicrobial peptides, lactoferrin and complement) and endogenous microflora. In addition, innate immune cells survey the environment for pathogen invasion by expression of a wide range of pattern recognition receptors.

  • Adaptive immunity in the genital mucosa is mediated by antibodies (IgG in vaginal transudate and IgA from the cervix), CD4+ T cells and CD8+ T cells. After viral clearance, foci of memory lymphocytes form near the vaginal epithelium, which provides an immediate source of virus-specific T and B cells, should a secondary infection occur.

  • Immune correlates of protection for each STV must be understood before a successful vaccine can be developed. Vaccines against HIV-1 must establish a robust local memory CD8+ T cell population without recruiting memory CD4+ T cells that can become targets for viral replication.

Abstract

Mucosal surfaces are exploited as a portal of entry into hosts by a wide variety of microorganisms. Over the past decade, an advanced understanding of the immune system of the gastrointestinal and the respiratory mucosae has been gained. However, despite the fact that many viruses are transmitted sexually through the genital tract, the immune system of the male and female genital mucosae has received much less attention. Here, I describe and highlight differences in the innate and adaptive immune systems of the genital and intestinal mucosae, and discuss some of the challenges we face in the development of successful vaccines against sexually transmitted viral pathogens.

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Figure 1: Effect of HIV-1 infection on human demographics.
Figure 2: Prevalence of genital herpes.
Figure 3: Anatomy of the genital mucosae and anorectal canal.
Figure 4: The innate defence system of the vaginal mucosa.
Figure 5: The adaptive immune system of the vaginal mucosa.

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Acknowledgements

A.I. is a recipient of the Burroughs Wellcome Fund (BWF) Investigators in the Pathogenesis of Infectious Disease award. This work was supported by a National Institutes of Health (NIH) grant to A.I. (R01AI054359, R01AI062428, R01AI064705, R21AI083242 and R01AI081884). The author would like to thank N. Iijima, H. Shin, E. Foxman, Y. Kumamoto and R. Medzhitov for review of this manuscript.

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    Akiko Iwasaki

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Glossary

Microfold cell

(M cell). A specialized epithelial cell that delivers antigens from the gut lumen directly to intraepithelial lymphocytes and subepithelial lymphoid tissues by transepithelial vesicular transport.

Transformation zone

The area that surrounds the border that is located between the endocervix and the ectocervix. This is where the columnar epithelial cells of the endocervix meet the stratified squamous epithelial cells of the ectocervix. It is the most common area for cervical cancer to develop.

Founder virus

A transmitted virus, or a virus that gives rise to all virus quasispecies in an infected individual.

Goblet cell

A mucus-producing cell that is located in the epithelial cell lining of the intestine and lungs.

Paneth cell

A cell that is present at the base of the crypts in the intestinal epithelium, which produces antimicrobial proteins and peptides, including phospholipase A2 and defensins.

γδ T cells

T cells expressing a T cell receptor that consists of a γ-chain and a δ-chain. These T cells are present in the skin, vagina and intestinal epithelium as intraepithelial lymphocytes. Although the exact function of γδ T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses.

Langerhans cells

A population of dendritic cells that are resident in the epidermal layer of the skin and in type II epithelia.

Pattern recognition receptors

(PRRs). Host receptors (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can detect pathogen-associated molecular patterns and initiate signalling cascades, leading to an innate immune response. These receptors can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5) and NLRs).

Virus-like particles

(VLPs). Virion-like structures that are formed from the self assembly of viral envelope or capsid proteins in vitro. VLPs are not infectious because they do not contain a viral genome.

TCID50

A typical virus infectivity assay that quantifies the amount of virus that is required to produce a cytopathic effect in 50% of inoculated tissue culture cells.

Cross-presentation

The mechanism by which certain antigen-presenting cells take up, process and present extracellular antigens on MHC class I molecules to stimulate CD8+ T cells.

Targeted lymph node immunization

A subcutaneous immunization technique that aims to administer a vaccine in the proximity of the internal and external iliac lymph nodes. This technique has been proposed as a means to harvest the naturally existing imprinting mechanism for instructing effector lymphocytes to migrate to the tissue (for example, the genital and rectal mucosae) that is being drained by a particular lymph node.

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Iwasaki, A. Antiviral immune responses in the genital tract: clues for vaccines. Nat Rev Immunol 10, 699–711 (2010). https://doi.org/10.1038/nri2836

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