Dendritic Cells Pulsed with a Recombinant Chlamydial Major Outer Membrane Protein Antigen Elicit a CD4⁺Type 2 Rather than Type 1 Immune Response That Is Not Protective

Abstract

Chlamydia trachomatis is an obligate intracellular bacterium that infects the oculogenital mucosae. C. trachomatis infection of the eye causes trachoma, the leading cause of preventable blindness. Infections of the genital mucosae are a leading cause of sexually transmitted diseases. A vaccine to prevent chlamydial infection is needed but has proven difficult to produce by using conventional vaccination approaches. Potent immunity to vaginal rechallenge in a murine model of chlamydial genital infection has been achieved only by infection or by immunization with dendritic cells (DC) pulsed ex vivo with whole inactivated organisms. Immunity generated by infection or ex vivo antigen-pulsed DC correlates with a chlamydia-specific interleukin 12 (IL-12)-dependent CD4 ؉ Th1 immune response. Because of the potent antichlamydial immunizing properties of DC, we hypothesized that DC could be a powerful vehicle for the delivery of individual chlamydial antigens that are thought to be targets for more conventional vaccine approaches. Here, we investigated the recombinant chlamydial major outer membrane protein (rMOMP) as a target antigen. The results demonstrate that DC pulsed with rMOMP secrete IL-12 and stimulate infection-sensitized CD4 ؉ T cells to proliferate and secrete gamma interferon. These immunological properties implied that rMOMP-pulsed DC would be potent inducers of MOMP-specific CD4 ؉ Th1 immunity in vivo; however, we observed the opposite result. DC pulsed ex vivo with rMOMP and adoptively transferred to naive mice generated a Th2 rather than a Th1 anti-MOMP immune response, and immunized mice were not protected following infectious challenge. We conclude from these studies that the immunological properties of ex vivo pulsed DC are not necessarily predictive of the immune response generated in vivo following adoptive transfer. These findings suggest that the nature of the antigen used to pulse DC ex vivo influences the Th1-Th2 balance of the immune response in vivo.

GM-CSF Transgene-Based Adjuvant Allows the Establishment of Protective Mucosal Immunity Following Vaccination with Inactivated Chlamydia trachomatis

“…Recently Shaw et al (29) reported that DCs pulsed with chlamydial major outer membrane protein or UVEB induced Ag-specific CD4 T cell proliferation in vitro, but that only immunization with DCs pulsed with UVEB induced Th1-mediated protective immunity in vivo. Immunization with DCs pulsed with major outer membrane protein elicited Th2 immune responses without significant protection against challenge infection.…”

“…Immunization with DCs pulsed with major outer membrane protein elicited Th2 immune responses without significant protection against challenge infection. The authors suggested that the nature of the Ag used to pulse DCs may influence the maturation of DCs and thereby skew the Th1-Th2 balance of the immune response in vivo (29). In the absence of maturation, Agloaded DCs may induce Ag-specific tolerance or polarize the immune response to a type 2 pattern (30).…”

Adoptive Transfer of CD8α+ Dendritic Cells (DC) Isolated from Mice Infected with Chlamydia muridarum Are More Potent in Inducing Protective Immunity Than CD8α− DC

“…For example, Su et al (37) and Shaw et al (38) have reported that adoptive transfer of whole Chlamydia organism-pulsed bone marrowderived DC induce strong Th1 responses and protection to challenge infection, while major outer membrane protein (MOMP)-pulsed bone marrow-derived DC induce Th2-type responses and failed to provide protection (48). In addition, these authors also found that the DC pulsed with whole chlamydial organism produce higher IL-12 than the DC pulsed with MOMP.…”

Induction of Enhanced Immunity to Intestinal Nematodes Using IL-9-Producing Dendritic Cells

“…Despite the wealth of literature examining the ability of ex vivo-primed DCs to sensitize against infectious diseases (3)(4)(5)(6)(7) and also the mechanisms that DCs initiate to prime immunity, there is little understanding of the role of DCs during intestinal nematode infection. It is clear that a Th2 immune response, characterized by the secretion of IL-4, IL-9, and IL-13 (8 -11), leads to complete expulsion of adult worms from the intestine, although the role of DCs in the induction of this response remains to be precisely determined.…”