The role of Chlamydia trachomatis specific HLA-E restricted CD8 T cell responses in clearance of infection

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PROJECT SUMMARY Chlamydia trachomatis (CT) infection remains the most prevalent bacterial sexually transmitted infection (STI) worldwide, with over 120 million new CT infections reported annually. In the US, African Americans and women are disproportionally affected by CT infection. Although over 1.5 million CT cases were recently reported in the US, this is likely an underestimation as the above-mentioned vulnerable population experiences inequities in access to routine healthcare. Women experience a greater burden of CT infection due to many reproductive complications associated with this infection. To date, prevention and control efforts have not significantly reduced CT infection rates. In addition, up to 20% of infected persons are reinfected within a year suggesting either a short lived or suboptimal immunity. In the context of both murine models and human studies, we and others have previously showed a role of IFN-γ-producing CD4+ T cells in chlamydia clearance and protection against reinfection. Recent studies in humans have however shown that CD8 T cells could play a role in CT infection as well. CD8 T cells recognize pathogens in the context of peptides presented by an infected cell via classical MHC- Ia alleles (in humans, HLA-A, B or C) or non-classical MHC-Ib alleles (in case of humans, HLA-E). Prior work has shown that HLA-E restricted CD8 T cells (HLA-E/CD8s) exert an important immune-regulatory role in control of several intracellular bacterial pathogens such as Mycobacterium and Salmonella. The role of HLA-E/CD8s in CT infection as it pertains to clearance of CT infection is unknown. Two previous human studies examining CD8 T cell responses to CT indirectly demonstrated responses restricted by non-classical HLA-I alleles. However, the precise nature of this restriction and the role of such cells in disease pathogenesis as it pertains to clearance of CT infection was not defined. Since HLA-Ia and HLA-Ib (i.e., HLA-E) are ubiquitously co-expressed, appropriate molecular tools and methodologies are needed to dissect the unique contributions of CD8 T cells responding to peptides presented via each of these alleles. We have recently generated HLA-E*01:01 and E*01:03 specific cellular resources that allowed us to identify HLA-E/CD8s and to assess their relevance in the context of CT infection. Specifically, our preliminary data shows that HLA-E/CD8s producing CD107a/IFN-γ/TNF- α are preferentially detected in women who clear CT infection. Our overall hypothesis is that HLA-E restricted CD8 T cells will play an important role in clearance of CT infection in women. In Aim 1, we will determine if CT-specific HLA-E restricted CD8 T cells play a role in the clearance of CT infection in women. In Aim 2, we will determine if CT-specific HLA-E restricted CD8 T cells can be primed from CT naïve female donors with no current or prior CT infection. In summary our completed studies will demonstrate the biological relevance and functionality of HLA-E restricted CD8 T cell response in clearance of CT infection and thus has direct applications for immunogen selection for a preventative CT based vaccine.