A new study by Miguel Relloso and colleagues from the Hospital General Universitario Gregorio Marañón in Madrid, Spain, identifies the female sex hormonesas important regulators of the T helper (Th)17 response induced by sperm, and related to dendritic cells (DCs), the key professional antigen-presenting cells.
Sperm is a foreign antigen (material) and its contact with the female reproductive tract elicits an immune/inflammatory response. Of note, the mucosal immune system of the female reproductive tract (FRT) must be uniquely prepared to maintain the balance between the presence of commensal microbiota, sexually transmitted pathogens and allogeneic spermatozoa.
Thus, insemination is followed by an influx of neutrophils to the mucosa of the FRT. In humans, semen was shown to induce a local recruitment of leukocytes, detected only after coitus without a condom. Moreover, the presence of antisperm antibodies in females has been widely reported.
Dendritic cells (DCs) are professional antigen-presenting cells in the mucosa of the FRT. Upon contact with exogenous ligands or inflammatory cytokines, DCs migrate to draining lymph nodes, thereby promoting T-cell activation and polarization.
For example, intracellular pathogens promote Th1 responses, and extracellular fungi and bacteria are very efficient at promoting Th17 responses. IL-17 is required for host defense against fungal infections, because IL-17 recruits neutrophils to the site of infection and neutrophils are the cells that clear fungal infections.
Sperm is considered as a weak immunogenic stimulus because it induces low IFN-γ levels, and in the female genital tract anti-sperm immunity has been linked almost exclusively to anti-sperm antibodies. Of note, male and female fungal infections are closely linked with infertility, which also generate high numbers of Th17 cells and high levels of IL-17A expression.
The group of Dr. Relloso hypothesized that the Th17 response could be linked to antisperm immunity. Thus, they investigated the Th17 antisperm response and found that sperm-primed DCs induce a Th17 response in the same way as do Candida albicans antigens.
Furthermore, they also hypothesized that female sex hormones can modulate the induction of the Th17 antisperm response to allow sperm to survive during ovulation. The investigators found that pretreatment with estradiol (E2) diminished the Th17 response, whereas pretreatment with diestrus hormones (progesterone [P] and lower E2) restored the pathogen-host equilibrium.
The investigators also set up C. albicans vaginal infections in hormonally treated ovariectomized mice. Three days after the inoculation, vaginal tissue was examined to detect C. albicans. E2-treated mice showed numerous filaments of C. albicans.
The investigators also detected lower levels of IL-17 and IL-22 in the sperm-pulsed co-culture supernatants after treatment with estrus levels of E2 compared with that after treatment with vehicle, P or diestrus levels of E2. Also, they detected low levels of IFN-γ in the sperm-pulsed co-cultures, in contrast to the C. albicans-pulsed co-cultures.
This study suggests that sperm-pulsed DCs are potent inducers of Th17 responses, and that the survival of the semen – the foreign material in the vagina, may depend mostly from the female hormonal status or environment. Thus, low Th17 response may allow the survival of allogeneic sperm, thus acquiring the ability to fertilize during estrus (with high E2 concentrations). During diestrus (low E2 and high P concentrations), DCs recover their antigen presentation efficiency.
In conclusion, while the role of fungal infections and Th17-related diseases in female infertility is well documented, the regulation of the Th17 response in antisperm immunity is poorly understood. This study is perhaps the first to link the Th17 response to anti-sperm immunity and its regulation by female sex hormones.
The authors propose that a robust and not-controlled Th17 response during estrus may represent an important factor that contributes to infertility. They also suggest that further insights into the hormonal regulation of the reproduction – infection balance and interactions may improve the diagnosis and treatment of fertility and infection problems related to the female genital tract.