Toll-like receptor (TLR)7 and TLR8 stimulation of mucosal-associated invariant T cells and gamma delta T cells: a role in HIV susceptibility

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Richard, Zipporah
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Abstract Host inflammation has been shown to increase the risk of HIV-1 acquisition. Innate T cells are positioned to respond early to infections and produce proinflammatory cytokines associated with end-organ inflammation and increased risk of HIV infection. Therefore, understanding the activation of innate T lymphocytes and their role in immune modulation and HIV infection is essential for developing an effective intervention against HIV transmission. Toll-like receptor (TLR) 7 and TLR8 are endosomal receptors that play an essential role in the immune response to viral infection. This Thesis compares Toll-like receptor (TLR) 7 and TLR8 responses in innate T cells in PBMCs from healthy blood donors. Hypothesis: TLR7 or TLR8 stimulation of PBMCs or monocyte-derived dendritic cells (MDDC) will lead to increased major histocompatibility complex (MHC) related protein 1 (MR1), which is a ligand for MAIT cell recognition on the membrane of antigen-presenting cells (APCs), and/or the expression of IL-12 and IL-18, activation of mucosal associated invariant T (MAIT) and gamma delta (γδ) T cells and cytokine expression Results: MAIT cells were highly activated by both TLR7 and TLR8, as evidenced by increased CD69 expression, but only TLR8 stimulation resulted in elevated cytokine responses. On the contrary, γδ T cells were found to be hyporesponsive to both TLR7 and TLR8 stimulation, as evidenced by reduced CD69 and cytokine responsiveness. In addition, TLR8 stimulation of PBMCs in the presence of interleukin 7 (IL-7) led to the expression of interferon-gamma (IFN-γ), suggesting TLR responses mediated via MAIT/γδ may be a key component in reduced susceptibility to HIV. Conclusion: These results demonstrate that although innate T cells are known to respond and protect against bacterial infections, they may also be activated during HIV infection, and their response may result in the activation of other immune cells resulting in enhanced HIV infection in vitro, supporting the overall hypothesis tested. Significance: This Thesis contributes to the growing knowledge of the outcomes of TLR7 and TLR8 stimulation and the role of MAIT and γδ T cell activation with respect to HIV infection, which could be critical information in the design of HIV vaccines, microbicides, or other interventions.
HIV, mucosal associated invariant T cells, gamma delta T cells, T cells, dendritic cells, monocytes, HIV susceptibility