The aim of the proposal is to construct an in vitro model of human cellular immune responses and to address fundamental questions on the link between vaccine adjuvants and the adaptive immune response. One emerging concept of adjuvant-stimulated immune activation is that monocytes are recruited from the blood to the injection site and differentiate into either macrophages or dendritic cells (DCs). The DC then migrate to the draining lymph nodes to activate adaptive immunity. The first objective is to construct an in vitro model to recapitulate this sequence of events and to study how adjuvants shape the adaptive immune response. This will be done through analysis of cytokine and chemokine induction and phenotypic characterization of DC activation. The second objective is to determine how innate activation in the in vitro model translates into primary CD4 T cell responses. This will be done using a candidate HIV vaccine as a model vaccine and focusing on the magnitude and the quality of the response using intracellular cytokine staining. Quality will be assessed through the polyfunctionality of HIV-specific CD4 T cells with particular emphasis on the production of IL-21 and MIP-1b by HIV-specific CD4 T cells. IL-21 is essential to prevent exhaustion of CD8 T cells during chronic infection and MIP-1b has an autoprotective effect of virus-specific CD4 T cells. The third objective is to evaluate how adjuvants affect recall responses in the context of antigenic variation. We will use different avian influenza H5N1 vaccines as models and focus on the link between quality and cross-reactivity of the CD4 T cell response - how do adjuvanted and non-adjuvanted ‘fish’ from a pool of antigenically related memory CD4 T cells. We will take advantage of the fact that the same individual can be immunized in vitro with either adjuvanted or non-adjuvanted vaccine, allowing direct comparison of the cross-reactive T cell receptor repertoires as a function of adjuvant.
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