ABSTRACT
Mucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to difficulties in disrupting the tolerogenic environment associated with mucosa, mucosal immunity remains difficult to stimulate through vaccines and requires appropriate adjuvants. We previously demonstrated that either administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses.
We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant.
First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the chorion while MamuLa-DR+ APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes.
Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+ high endothelial venules in their lower FGT sampled 2 weeks after the last immunization.
Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA plasma cells in the mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Contribution to the Field Statement
Mucosal immune responses are essential to protect against pathogens entering through mucosal surfaces. However, the development of mucosal immunity remains difficult to stimulate and requires effective mucosal adjuvants.
We have previously evidenced a new function for IL-7. Overexpressed in the intestines of acutely SIV-infected macaques, IL-7 stimulates the recruitment of immune cells into infected tissues, contributing to the development of the immune responses, suggesting its possible use as a mucosal adjuvant.
We have showed here that non-traumatic vaginal administration of recombinant glycosylated simian IL-7 to macaques prior to antigen administration, allows the development of a strong mucosal immune response, through the local recruitment of immune cells induced by local expression of chemokine, the activation of mDCs and the formation of tertiary lymphoid structures in the vaginal mucosa. The mucosal localization of antigen-specific IgA plasma cells argues for their contribution to the high levels of specific IgAs evidenced in vaginal secretions.
We thus conclude that IL-7, already used in clinics without major adverse effects, can serve as an adjuvant to stimulate the mucosal immune system of the female genital tract and induce vaginal antibody responses following local immunization, most likely the best way to protect against sexually transmitted diseases.