Mechanistic investigations of TLR4 adjuvant effects on γ9δ2 T cells 4517

Abstract Description γδ T cells provide protective effects against infectious diseases and cancer. We reported that the current vaccine for Tuberculosis (TB), BCG, induces memory γ9δ2 T cells. Those memory T cells can be expanded by the Mycobacterium tuberculosis antigen 6-O-methylglucoselipopolysaccharide (mGLP) to inhibit intracellular mycobacterial growth. MGLP also induced protection in a non-human primate model of TB. However, γδ T cell in vitro and in vivo expansion requires IL-2. IL-2 has multiple drawbacks for adjuvant use, including preferential induction of Tregs and autoimmune stimulation, requiring the identification of safer adjuvants that promote γδ expansion. We recently demonstrated that the synthetic TLR4 adjuvant, Glucopyranosyl Lipid A (GLA), promotes expansion of mGLP and phosphoantigen reactive γδ T cells. In vitro expansion assays were initially performed using PBMCs with and without dendritic cells stimulated with antigen and either IL-2 or novel adjuvants. The absolute numbers of expanded effector γδ T cells were calculated using flow cytometry after 7 days of culture and novel adjuvant responses compared to IL-2. We report the optimal cellular requirements for GLA to promote γδ T cell expansion include dendritic cells and monocytes. These results have broad implications for development of vaccines targeting γδ T cells and suggest mGLP combined with the adjuvant GLA may activate and expand γ9δ2 T cells protective against TB in humans. Funding Sources Supported by NIAID/NIH R01AI048391; Bill & Melinda Gates Foundation OP1118659 Topic Categories Vaccines and Immunotherapy (VAC)