Protective role of TH17 cells in an FcγR targeting immunization strategy against the respiratory bacterial pathogen, Francisella tularensis

Abstract

Abstract Francisella tularensis is a category A intracellular bacterial pathogen with no FDA approved vaccine. Understanding the immunological mechanisms involved in host defense can improve vaccine efficacy. Previously we have shown using an F. tularensis murine infection model that targets the inactivated bacterium (iFt) to Fcγ receptors on antigen presenting cells (APCs) using anti-LPS monoclonal antibodies (mAb-iFt) provides full protection against lethal pulmonary challenge with F. tularensis live vaccine strain (LVS). The protection provided by this mucosal vaccine strategy involves both innate and adaptive immune components, with a strong inflammatory response being critical for protection. This study focuses on elucidating the role of Th 17 cells, a T helper cell subpopulation involved in pathology and host defenses against bacterial pathogens. C57BL/6 mice were immunized with iFt and mAb-iFt on day 0 and 21 and then challenged i.n. with a lethal dose of LVS on day 35. Flow cytometry data revealed a significant population of Th17 cells (characterized as CD3+/CD4+/IL- 17a+/RORγ-T+ cells) in the lungs and spleen post-infection in the mAb-iFt immunized group when compared to PBS and iFt alone. Additionally, cytokine levels of IL-6 and TGF-β1 (two known synergistic Th17 polarizing cytokines) were elevated in the lungs and spleens of mAb-iFt immunized mice on days 2 and 5 post-infection when compared to iFt alone. Lastly, cytokine levels of IL-17a, an effector cytokine secreted predominantly by active Th17 cells, was shown to be significantly increased in mAb-iFt immunized mice when compared to iFt alone. Collectively, our data suggests that Th17 cells possess a protective role in the immune response to pulmonary F. tularensis infection.