Chlamydia-Specific CD4 T Cell Clones Control Chlamydia muridarum Replication in Epithelial Cells by Nitric Oxide-Dependent and -Independent Mechanisms

Abstract

Chlamydia trachomatis serovars D–K are sexually transmitted intracellular bacterial pathogens that replicate in epithelial cells lining the human reproductive tract. It is clear from knockout mice and T cell depletion studies using Chlamydia muridarum that MHC class II and CD4 T cells are critical for clearing bacteria from the murine genital tract. It is not clear how CD4 T cells interact with infected epithelial cells to mediate bacterial clearance in vivo. Previous work using an epithelial tumor cell line showed that a Chlamydia-specific CD4 T cell clone was able to inhibit C. muridarum replication in vitro via induction of epithelial NO production. We have previously shown that Chlamydia-specific CD4 T cell clones can recognize and be activated by infected reproductive tract epithelial cells and block Chlamydia replication in them. We extend those observations by investigating the mechanism used by a panel of CD4 T cell clones to control Chlamydia replication in epithelial cells. We found that Chlamydia-specific CD4 T cell clones were cytolytic, but that cytolysis was not likely critical for controlling C. muridarum replication. For one, CD4 T cell clone-induced epithelial NO production was critical for controlling replication; however, the most potent CD4 T cell clones were dependent on T cell degranulation for replication control with only a minor additional contribution from NO production. We discuss our data as they relate to existing knockout mouse studies addressing mechanisms of T cell-mediated control of Chlamydia replication and their implications for intracellular epithelial pathogens in mouse models.

PmpG 303-311 , a Protective Vaccine Epitope That Elicits Persistent Cellular Immune Responses in Chlamydia muridarum-Immune Mice

“…2B). PmpG1.1 terminates C. muridarum replication in epithelial cells with an efficiency comparable to those of other potent previously described Chlamydia-specific CD4 T cell clones (10).…”

“…That time point occurs after the C. muridarum elementary body (EB)-to-reticulate body (RB) transition is well under way and supports our previous hypothesis that protective immunity is not likely based on nonspecific disruption of epithelial cell physiology or viability during the "eclipse phase" ϳ2 to 15 h postinfection, when noninfectious RB predominate in the infected cell. Rather, protective CD4-mediated T cell immunity is more likely a direct attack on intracellular infectious EB (10).…”

Evaluation of a multisubunit recombinant polymorphic membrane protein and major outer membrane protein T cell vaccine against Chlamydia muridarum genital infection in three strains of mice

“…B cells and antibody play a more limited role by enhancing CD4 T cell priming and preventing spread of infection [18]. Clearance of infection from mucosal epithelial cells depends on local cellular immune responses [28, 29]. Selection of molecularly defined antigens for a subunit vaccine that stimulate CD4 Th1 cells is an essential first step in the current design effort.…”

Subunit vaccines for the prevention of mucosal infection with Chlamydia trachomatis

“…The second CD4-mediated Chlamydia replication termination mechanism was identified by Johnson’s group in 2010 [23] and is dependent on a subset of CD4 T cells that express a granule associated protein called Plac8. This mechanism like iNOS dependent immunity relied on T cell-epithelial cell contact followed by T cell degranulation and was only seen in Chlamydia -specific CD4 T cells that expressed Plac8 [22].…”