Mucosal Infection With Chlamydia and the CD4+ T Cell Response

Abstract

Chlamydia trachomatis is the most commonly reported sexually transmitted infection in the United States. A deeper understanding of protective immune responses is necessary to develop a vaccine that prevents the inflammatory diseases associated with Chlamydia infection. In this dissertation, I first aimed to characterize the protective aspects of the CD4+ T cell response to C. trachomatis. I found that OT-II T cells do not effectively clear an engineered C. trachomatis strain expressing the heterologous antigen ovalbumin. In contrast, NR1 T cells (specific for the C. trachomatis protein Cta1) rapidly clear infection, suggesting that there may be key differences in these two antigens to elicit a protective immune response. IFNg production is critical for Chlamydia clearance, so I next explored the importance of NR1 T cell mediated IFNg production and sensing during C. trachomatis infection. I found that NR1 T cells home to specific sections in the genital tract that contain bacteria in a process that is independent of IFNg production or sensing, but that bacterial clearance is dependent on IFNg production by NR1 T cells or endogenous cells. I next characterized memory and naïve NR1 T cell populations following secondary infection. I found that naïve NR1 T cells are more proliferative than memory NR1 T cells but memory NR1 T cells are specifically inhibited in the absence of IFNg via an unknown mechanism. Overall, these data provide insight into the antigen-specific CD4+ T cell response and its role in clearing C. trachomatis infection. Understanding the initial interactions between Chlamydia and the host is also critical for developing strategies to combat colonization. In the second part of this dissertation, I found that C. trachomatis initially associates with neutrophils and CD103- dendritic cells. These dendritic cells were previously found to play an important role in inducing a protective antigen-specific CD4+ T cell response in the genital tract. I also found that transcervical infection with C. muridarum elicits a more inflammatory response correlating with initially higher bacterial burdens. This work further elucidates the varying immune responses in mouse models of Chlamydia infection and will ultimately enhance our ability to develop a protective vaccine.