Research Article

A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells

Science  19 Jun 2015:
Vol. 348, Issue 6241,
DOI: 10.1126/science.aaa8205

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The right combination for protection

Despite its prevalence, no vaccine exists to protect against infection with the sexually transmitted bacterium Chlamydia trachomatis. Stary et al. now report on one potential vaccine candidate (see the Perspective by Brunham). Vaccinating with an ultraviolet light-inactivated C. trachomatis linked to adjuvant-containing charged nanoparticles protected female conventional and humanized mice against C. trachomatis infection. The vaccine conferred protection only when delivered through mucosal routes. Protection relied on targeting the bacteria to a particular population of immunogenic dendritic cells and inducing memory T cells that resided in the female genital tract.

Science, this issue 10.1126/science.aaa8205; see also p. 1322

Structured Abstract


Administering vaccines through nonmucosal routes often leads to poor protection against mucosal pathogens, presumably because such vaccines do not generate memory lymphocytes that migrate to mucosal surfaces. Although mucosal vaccination induces mucosa-tropic memory lymphocytes, few mucosal vaccines are used clinically; live vaccine vectors pose safety risks, whereas killed pathogens or molecular antigens are usually weak immunogens when applied to intact mucosa. Adjuvants can boost immunogenicity; however, most conventional mucosal adjuvants have unfavorable safety profiles. Moreover, the immune mechanisms of protection against many mucosal infections are poorly understood.


One case in point is Chlamydia trachomatis (Ct), a sexually transmitted intracellular bacterium that infects >100 million people annually. Mucosal Ct infections can cause female infertility and ectopic pregnancies. Ct is also the leading cause of preventable blindness in developing countries and induces pneumonia in infants. No approved vaccines exist to date. Here, we describe a Ct vaccine composed of ultraviolet light–inactivated Ct (UV-Ct) conjugated to charge-switching synthetic adjuvant nanoparticles (cSAPs). After immunizing mice with live Ct, UV-Ct, or UV-Ct–cSAP conjugates, we characterized mucosal immune responses to uterine Ct rechallenge and dissected the underlying cellular mechanisms.


In previously uninfected mice, Ct infection induced protective immunity that depended on CD4 T cells producing the cytokine interferon-γ, whereas uterine exposure to UV-Ct generated tolerogenic Ct-specific regulatory T cells, resulting in exacerbated bacterial burden upon Ct rechallenge. In contrast, mucosal immunization with UV-Ct–cSAP elicited long-lived protection. This differential effect of UV-Ct–cSAP versus UV-Ct was because the former was presented by immunogenic CD11b+CD103 dendritic cells (DCs), whereas the latter was presented by tolerogenic CD11bCD103+ DCs. Intrauterine or intranasal vaccination, but not subcutaneous vaccination, induced genital protection in both conventional and humanized mice. Regardless of vaccination route, UV-Ct–cSAP always evoked a robust systemic memory T cell response. However, only mucosal vaccination induced a wave of effector T cells that seeded the uterine mucosa during the first week after vaccination and established resident memory T cells (TRM cells). Without TRM cells, mice were suboptimally protected, even when circulating memory cells were abundant. Optimal Ct clearance required both early uterine seeding by TRM cells and infection-induced recruitment of a second wave of circulating memory cells.


Mucosal exposure to both live Ct and inactivated UV-Ct induces antigen-specific CD4 T cell responses. While immunogenic DCs present the former to promote immunity, the latter is instead targeted to tolerogenic DCs that exacerbate host susceptibility to Ct infection. By combining UV-Ct with cSAP nanocarriers, we have redirected noninfectious UV-Ct to immunogenic DCs and achieved long-lived protection. This protective vaccine effect depended on the synergistic action of two memory T cell subsets with distinct differentiation kinetics and migratory properties. The cSAP technology offers a platform for efficient mucosal immunization that may also be applicable to other mucosal pathogens.

Protection against C. trachomatis infection after mucosal UV-Ct–cSAP vaccination.

Upon mucosal vaccination, dendritic cells carry UV-Ct–cSAP to lymph nodes and stimulate CD4 T cells. Effector T cells are imprinted to traffic to uterine mucosa (first wave) and establish tissue-resident memory cells (TRM cells). Vaccination also generates circulating memory T cells. Upon genital Ct infection, local reactivation of uterine TRM cells triggers the recruitment of the circulating memory subset (second wave). Optimal pathogen clearance requires both waves of memory cells.


Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ–producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)–inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct–cSAP targeted immunogenic uterine CD11b+CD103 dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11bCD103+ DCs. Regardless of vaccination route, UV-Ct–cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (TRM cells). Optimal Ct clearance required both TRM seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct–cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties.

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