CHARACTERIZATION OF INTERACTIONS OF PROTECTIVE CHLAMYDIA-SPECIFIC CD4 T CELLS WITH PATHOGENIC CD8 T CELLS AFTER GENITAL CHLAMYDIA INFECTION

Project: Research project

Project Details

Description

Chlamydia trachomatis is the leading cause of sexually transmitted bacterial disease worldwide. Within the U.S., approximately 3 million new cases of genital chlamydial infection are reported annually (1). Significant efforts are being made to develop a vaccine to prevent female reproductive pathology. Historical trials of a Chlamydia vaccine demonstrated early efficacy in reducing incidence of infection, but exacerbation of immunopathologies in the long term in vaccinated compared to non-vaccinated individuals(12). This emphasizes the importance of understanding the mechanisms of chlamydial immunopathogenesis, and utilizing such information to guide the development of an efficacious, but safe, anti-chlamydial vaccine. The mouse model of genital infection with Chlamydia muridarum recapitulates most aspects of human STI with C. trachomatis (8). Furthermore, affected mice display infertility similar to a subset of infected and untreated human females.Cell-mediated immune responses play a dominant role in the resolution of chlamydial genital tract infection. The use of adoptive transfer and monoclonal antibody-mediated in vivo depletion have clearly identified CD4 T cells as a population of cells required for the resolution of genital tract infection in experimental models of chlamydial infection. Intranasal Chlamydia live EB immunization provides near-total protection against pathology following challenge. The role of CD8 T cells in chlamydial clearance has been explored for over two decades without much success until recently. We demonstrated that CD8 T cells contribute significantly to chlamydial UGT pathology via the production of TNF-α. Additionally, we have recently demonstrated that antigen-specific, not bystander, CD8 T cells are responsible for such pathogenic effects (3). We further evaluated the downstream mediators, TNF receptor (TNFR) 1 and TNFR2, and found that while both contribute to chlamydial pathologies, CD8 T cell mediated immunopathogenesis was dependent upon expression of TNFR2-, but not TNFR1, on CD8 T cells, and TNFR2 is important for CD8 T cell activation (5).The accumulated evidences show the interactions of CD4 and CD8 T cells during bacteria and virus infection. CD4 can be involved in a multitude of ways in (A) CD4 T cells can be critical in catalyzing recruitment and/or entry of CD8 T cells primed in draining lymphoid tissue to localized infections, such as that of vaginal tissue(14). (B) CD4 T cells regulate CD8 T cells at numerous levels, including expansion, migration, effector function, survival, and establishment of memory (15). (C) antigen-specific CD4 T cells can indeed suppress the proliferation of antigen-specific naive CD8 T cells in response to low doses of vesicular stomatitis virus (17). Such interactions have also been shown that CD4 T cell-released exosomes inhibit CD8 cytotoxic T-lymphocyte responses and antitumor immunity (16). Therefore, it is quite reasonable to explore such interactions between antigen-specific CD4 and CD8 T cells in context of chlamydial immunopathogenesis.

StatusFinished
Effective start/end date2/7/209/30/21

Funding

  • National Institute of Food and Agriculture: $1,442,481.00

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