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

Abstract

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.

CD4+ T Cell Priming as Biomarker to Study Immune Response to Preventive Vaccines

“…Antigen-specific CD4 + T cell clonal expansion was indeed detected in iliac LNs, and proliferated T cells disseminated toward distal LNs and spleen, similarly to what observed following nasal immunization (38). These data show that vaginal immunization is efficient in eliciting CD4 + T priming despite the absence of an organized mucosa-associated inductive site in the genital tract (Figure 2).…”

“…This has encouraged the use of TLRs ligands as promising adjuvants (10, 29–33), that can influence the effector fate of antigen-specific primed CD4 + T cells (10). CD4 + T cell priming has been studied for characterizing the mechanism of action of adjuvants such as alum (34), the CpG ODN (35), the lipopolysaccharide (36) or its derivative-like monophosphoryl lipid A (37), cholera toxin (38), or its B subunit (CTB) (39, 40). …”

“…CD4 + T cell priming following immunization by different mucosal routes has been characterized in the murine model (35, 38, 43–45) as discussed in the next section. Recently, we have also demonstrated that the route used for priming, but not for booster immunization, influences the skewing of the CD4 + T effector response toward Th1 or Th2 with a stronger Th1 polarization upon nasal administration compared to the systemic one (46).…”

“…T cell priming was also studied following vaginal immunization in hormone synchronized mice, showing a very efficient activation of CD4 + T cells (38, 63). Antigen-specific CD4 + T cell clonal expansion was indeed detected in iliac LNs, and proliferated T cells disseminated toward distal LNs and spleen, similarly to what observed following nasal immunization (38).…”

Mucosal vaccines

“…67 In clinical settings, however, an intravaginal boost was required to attract T cells to the genital tract after i.n immunization with the cholera toxin coupled to OVA. 68 Additionally, oral, nasal or intravaginal immunization with CTB were able to induce comparable secreted IgA levels in the vaginal tract but no cellular immune responses. 69 In fact, inducing mucosal immunity at different anatomical sites after local priming may vary according to the specific mucosal tissue, type of immune response or vaccination approach.…”