Type

Range

Units

Status

Start Date

End Date

Financing

Keywords

Partner

Brief description/objective

The adaptive immune system protects us from infectious viruses and other microbes. Cells of the adaptive immune system ‐ lymphocytes and antigen‐presenting cells (APC) ‐ are highly organized in strategic tissue locations throughout the body, the secondary lymphoid organs (SLO), such as peripheral lymph nodes (PLN) and spleen. The roles of SLO are i) to filter pathogens from blood and lymph, thereby retaining their spread through the body; ii) to present pathogens or derived peptides to antigen‐specific lymphocytes; and iii) to create microenvironments, which regulate the differentiation and survival of antigen‐specific lymphocytes. Inside SLO, T and B lymphocytes separate into particular microenvironments created by stromal cells,
where they scan APC with high motility. When specific antigens are encountered, the trafficking patterns of lymphocytes change, accompanied by a stromal reorganization of the entire SLO structure. T and B cells start interacting for efficient immune responses, while affected SLO can increase several fold in size. This
may ultimately result in a temporary loss of defined T and B cell zones and immune responsiveness. The stromal cells which form the scaffold of T and B cell zones, the fibroblastic reticular cells (FRC) and follicular dendritic cells (FDC), respectively, are now recognized to participate in all of these processes. Novel imaging techniques such as twophoton microscopy (2PM), which allows to directly observe the dynamic behavior of lymphocytes and APC in PLN of live, anesthetized mice, have uncovered a role of FRC as contact guidance cues for migrating lymphocytes. Furthermore, FRC secrete promigratory and prosurvival factors and may be involved in antigen presentation. Nonetheless, there are significant unmet needs in this research field, encompassing i) lack of scientific knowledge on the role of stromal cells in homeostasis and antiviral immunity, ii) lack of research tools which permit in vivo analysis of stromal cell
biology, and iii) lack of researchers with expertise in the field to address these and future open questions.
In summary, our proposal aims to address the immunological relevance of stromal elements of PLN with microscopic (2PM) and mesoscopic (OPT/SPIM) imaging. As SLO are the prime site for therapeutic and prophylactic immune interventions, elucidating the cellular and molecular mechanisms of SLO plasticity may allow identifying new avenues for therapeutic and preventive immunotherapy.