The immune response to infection consists of complex interplays between pathogens, innate and adaptive immunity and aims in eradication of the pathogens with least damage to the host. Thereby, the immune system has evolved to resist a wide variety of invading pathogens, and further specialized in vertebrates with the development of highly organized secondary lymphoid tissues (Lymph Nodes (LN), spleen, tonsils). Despite these sophisticated mechanisms, some infectious agents (i.e. HIV or tuberculosis) developed mechanisms to resist and even exploit the host immune response and become persistent. For retroviral infection studies, non-human primates and humanized mouse models represent the animal models of choice. Both models exhibit limitations and there are efforts to replace the use of non-human primates in biomedical research due to ethical and scientific reasons (“Three Rs” concept of Replacement, Refinement and Reduction of animal use for experimental purposes). As an alternative approach we therefore want to design a 3-dimensional T cell zone of human LN during the project period to further dissect host-pathogen interactions and immunological processes during HIV infection. Human 3D systems are superior to cell culture monolayer, which lack the whole organ complexity and show limitations respecting long term cultures. The in vitro 3D system, engineered during the project period, will allow to exactly characterise the function of different dendritic cell (DC) subsets and opsonisation patterns in immune response initiation against retroviral infections. Analysing DC/T cell interactions enrolling the opsonisation pattern of HIV-1 in more detail in a setting close to reality is a key issue in the field of HIV pathogenesis. Novel findings in this project are potentially also transformed to other scientific areas or industrial applications (i.e. drug screening, vaccination technologies).
Objectives are to design the lymph node by 3D bioprinting and optimizing conditions of the FRC network within 3D bioprinted tissues. CCL21/CCL19 gradients will guide Ag-loaded DCs to the optimized FRC network, which will then be loaded with naïve, autologous T cells. Cell-Cell interactions will be monitored using e.g. high-content screening, single-cell RNAseq, live cell analyses, or scanning electron microscopy
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