Identification of adjuvants for γδ T cells in response to a novel M. tuberculosis vaccine antigen

Abstract

Abstract γδ T cells are ideal effector cells against infectious diseases and cancer. They reside in blood, lymphoid organs, and mucosa, readily available for host defense. γδ T cells develop memory responses independent of MHC presentation. They perform immune functions such as cytolysis, cytokine production, antigen presentation, dendritic cell maturation, and promotion of B cell and T cell responses. Our lab reported that γδ T cells responsive to M. tuberculosis-specific 6-O-methylglucose-containing lipopolysaccharides (mGLP) inhibit intracellular mycobacterial growth. Preliminary data from NHP studies indicate that vaccination with mGLP and IL-2 greatly reduces Mtb burden post-challenge. IL-2 is not translatable for adjuvant use in humans. Therefore, novel adjuvants for γδ T cells are needed to develop optimal vaccine strategies. We are investigating adjuvant candidates to determine their ability to induce optimal activation and expansion of γδ T cells with mGLP or the phosphoantigen HMBPP. To screen adjuvants, PBMCs are incubated with antigen and adjuvant for 7 days, then analyzed for expansion of γδ T cells. Initially few adjuvants promoted γδ T cell expansion in response to HMBPP and none to mGLP. When matured monocyte-derived DCs were added, multiple adjuvants promoted γδ T cell expansion in response to HMBPP and mGLP stimulation without IL-2. We will determine mechanisms involved in novel adjuvant activity, whether adjuvant and mGLP-expanded γδ T cells inhibit intracellular mycobacterial growth, identify cytokines involved in candidate adjuvant effects, characterize cell surface markers upregulated on DC and γδ T cells, and test the best candidate adjuvant(s) with mGLP in NHP trials. Supported by Gama Delta R01 AI048391