Experimental studies of local immunity in the female genital tract with special reference to immune protection against Chlamydia trachomatis infection

Chlamydia trachomatis is an obligate intracellular pathogen that infect ocular and genital tract mucosal tissues. It can cause trachoma, which is one of the worlds major causes of preventable blindness. Chlamydial genital tract infection is one of the most common sexually transmitted diseases (STD) which cause pelvic inflammatory disease, infertility or ectopic pregnancy. This thesis investigates the major protective factors against a genital tract infection with Chlamydia trachomatis. We have used a human serovar of Chlamydia trachomatis and genetically engineered knockout mice lacking important constituents of the immune system. We found that the CD4-deficient mice were less well protected against a challenge with live bacteria following clearance of a primary infection compared with CD8-deficient or wildtype mice, suggesting that the development of protection against a reinfection with C. trachomatis requires CD4+ T cells rather than CD8+ T cells. Protection was primarily conferred by IFNg since mice lacking the IFN-g-receptor were unable to develop protection against reinfection. Moreover, IL-4-deficient mice, with an impaired Th2 system, developed the same level of protection as did the wild type mice. Poor protection was not due to a lack of local antibodies since the IFN-gR-deficient mice exhibited 10-times higher levels of local IgA than wildtype mice did. This was conclusively demonstrated in B cell-deficient mice which were well protected against reinfection. Furthermore, in the complete absence of antibodies protection was found to be long lived, indicating that immunological memory can develop independently of B cells. Finally, the presence and participation of T cells locally in the genital tract mucosa was analyzed in detail using RT-PCR, FACS and immunohistochemistry. The naive mucosa was dominated by a population of CD3+B220+ T cells expressing the ab TCR. Although the naive mucosa hosted few CD4+ or CD8+ T cells, a large increase in these cell populations could be detected following genital tract infection with C. trachomatis. At an early stage of infection we observed IFN-g mRNA expression that correlated with the increase in T cells in the genital tract of immune mice. This finding demonstrated that a protective immune response is rapidly triggered in response to a challenge infection even at 6 mo. following the resolution of a primary infection.These results demonstrate that protective immunity against a genital tract infection with Chlamydia trachomatis is dependent on Th1 CD4+ T cells and IFN-g. B cells, and thus antibodies, are not required for the clearance or development of complete protection against C. trachomatis. Immunological memory and long term protection against severe infection can develop even in the absence antibodies as seen in the B cell-deficient mMT mice. Protection is associated with a rapid IFN-g production and influx of CD4+ T cells and into the genital tract mucos