| To defend against some diseases, like intracellular pathogens, the immune system must orchestrate T cell-mediated lysis of infected cells. Vaccines which trigger T cell immunity, however, are not readily available due to a lack of adequate and appropriate adjuvants. Current adjuvants either help generate B cell memory, or are too toxic for clinical use. Recently, it has been discovered that an innate-like population of cells, Natural Killer T cells (NKT), can be stimulated by a single ligand, alphaGalCer, and provide adjuvant effects to T cell vaccines in mice. Because of the significant differences between mice and human immunology, we sought to test whether this potential could be translated to human cells. Here, human NKT cells were activated with alphaGalCer and used to boost the processes of T cell memory generation in-vitro. Priming of T cell memory was enhanced by the maturation of potent antigen presenting cells called dendritic cells (DCs). NKT cell activation also enhanced the cytotoxic potential of the differentiating T cells. To emphasize the feasibility of triggering these responses clinically, endogenous NKT cells were activated within in-vitro cultures of adult human peripheral blood mononuclear cells (PBMCs), providing similar adjuvant effects. A humanized mouse, with a functional human immune system, was generated to test these principles in-vivo. Differentiation of human fetal hematopoietic stem cells (HSCs) into multiple immune populations, including T cells, was facilitated by the surgical implantation of a human thymic tissue fragment. While enabling T cell education, this thymic organoid also spurred the development of a pathology resembling human chronic graft-vs.-host disease (GVHD). A decrease in regulatory T cell (Treg) frequency within the thymic environment correlated with the onset of GVHD. When younger fetal tissue was used, however, GVHD was delayed, possibly in connection with their enhanced capacity for Treg differentiation. Finally, humanized mice were used to test NKT cell activation as an adjuvant in a vaccine for Epstein-Barr virus (EBV), resulting in some unexpected results. However, the adjuvant abilities of NKT cell activation have significant potential for enhancing T cell vaccines, providing a much needed resource for protection against life-threatening diseases. |
