Georg Stary, Andrew Olive, Aleksandar F. Radovic-Moreno, David Gondek, David Alvarez, Pamela A. Basto, Mario Perro, Vladimir D. Vrbanac, Andrew M. Tager, Jinjun Shi, Jeremy A. Yethon, Omid C. Farokhzad, Robert Langer, Michael N. Starnbach, Ulrich H. von Andrian. (2015). A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science (348) 6241. DOI: 10.1126/science.aaa8205.
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 CD11b–CD103+ 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.
Gondek DC, Olive AJ, Stary G, Starnbach MN. “CD4+ T Cells Are Necessary and Sufficient To Confer Protection against Chlamydia trachomatis Infection in the Murine Upper Genital Tract.” J Immunol. 2012 189:2441-2449; published ahead of print August 1, 2012, doi:10.4049/jimmunol.1103032
Chlamydia trachomatis infection is the most common bacterial sexually transmitted disease in the United States. Chlamydia infections that ascend to the upper genital tract can persist, trigger inflammation, and result in serious sequelae such as infertility. However, mouse models in which the vaginal vault is inoculated with C. trachomatis do not recapitulate the course of human disease. These intravaginal infections of the mouse do not ascend efficiently to the upper genital tract, do not cause persistent infection, do not induce significant inflammation, and do not induce significant CD4(+) T cell infiltration. In this article, we describe a noninvasive transcervical infection model in which we bypass the cervix and directly inoculate C. trachomatis into the uterus. We show that direct C. trachomatis infection of the murine upper genital tract stimulates a robust Chlamydia-specific CD4(+) T cell response that is both necessary and sufficient to clear infection and provide protection against reinfection.