Mechanisms of immunosuppression induced by Chlamydia trachomatis

Abstract

Chlamydia trachomatis is an obligate intracellular bacterial pathogen that if left untreated, can cause reproductive harm. Failure of natural adaptive immunity to this pathogen results in chronic and repeat infections. In efforts to understand failure of adaptive immunity, we have previously discovered that CD8+ T cells, normally integral for controlling intracellular pathogen infections, are misprogrammed by PD-1/PD-L1 signaling during C. trachomatis infection and fail to mount a protective response. Here we sought to uncover the host pathways and bacterial factors involved in PD-L1 upregulation that may lead to CD8+ T cell inhibition. We discovered that a secreted factor produced during C. trachomatis infection is sufficient to induce PD-L1 upregulation. Using both in vitro and in vivo infection models, we identified this factor as type I interferons (IFNs). Based on previous work showing that stimulator of interferon genes (STING) plays a critical role in driving type I IFN expression during C. trachomatis infection, we show that STING is required for type I IFN-driven PD-L1 upregulation during infection in vitro. Both dsDNA sensing by cyclic GMP-AMP synthase (cGAS) upstream of STING and direct sensing of bacterial cyclic dinucleotides by STING contribute to type I IFN-driven PD-L1 upregulation during C. trachomatis infection. Finally, we explored the C. trachomatis factors involved in inducing type I IFN-driven PD-L1 upregulation. We show that PD-L1 expression is dependent on C. trachomatis development within host cells and its type III secretion system (T3SS) but independent of genes encoded on the C. trachomatis plasmid. Given that DacA is the diadenylate cyclase enzyme responsible for producing the cyclic dinucleotide c-di-AMP in Chlamydia, we hypothesize that this specific C. trachomatis factor contributes to STING activation and downstream type I IFN-driven PD-L1 upregulation. Taken together, our data supports a model in which T3SS activity during C. trachomatis infection delivers dsDNA and c-di-AMP produced by DacA into the host cytosol to activate STING and induce type I IFN-driven PD-L1 upregulation. These findings illuminate a mechanism by which C. trachomatis infection may impair CD8+ T cell mediated immunity.