Mechanisms of human Th17 cell differentiation and their role in HIV infection

Balanced immune response and regulation is critical to protect the host against pathogens while preventing autoimmunity. The regulatory (Treg) and Th17 subsets of T cells play opposing roles in suppressing immune response versus inducing inflammation, respectively. Th17 cells secrete proinflammatory cytokine IL-17 and protect the host against bacterial or fungal infections especially at the mucosal tissues. However, Th17 cells are also implicated in the pathogenesis of many autoimmune disorders. Therefore the immune system finely regulates the responses of Th17 and other subsets that promote excess inflammation or self-reactivity.;The central goal of this dissertation is to understand how Th17 cells differentiate and how they functionally impact the immune response. Given the importance of this subset, we also asked their status and role during HIV infection, which is characterized by both chronic immune activation and eventual immunodeficiency. We found that Th17 cells expressed HIV-co receptor CCR5 and produced very low levels of CCR5 ligands. As a consequence, Th17 cells were highly susceptible to HIV infection in in vitro infection assays. We also found reduction in the percent of Th17 cells in HIV-infected individuals. However, this was paradoxically observed in people under anti-retroviral treatment, rather than treatment naive subjects. Also, CCR5+ Th17 depletion correlated with higher level of immune activation marker, CD38, which is one of the best biomarkers for disease progression.;The second goal of this thesis was focused on determining the mechanisms of Th17 cell regulation. We found that signals from TGFbeta are important in suppressing IL-17 secretion and inducing the Treg transcription factor Foxp3 in Th17 cells. Furthermore, we identified a metalloprotease specifically expressed on Th17 cells that may be involved in regulation of TGFbeta signals in this subset and Treg cells.;Our findings have implications for understanding the contribution of Th17 cell perturbation during HIV infection and also for fine-tuning immune responses to avoid chronic harmful inflammation and auto-reactivity.