Thesis Saskia van Asten

Summary

The immune system is in charge of clearing the human body of pathogens and tumor cells to prevent, resolve or mitigate disease. To fulfill this task it employs many different cell types with unique capabilities, as each threat requires a different strategy to ensure clearance. Intercellular communication is of vital importance to activate or inhibit the appropriate (immune) cells at the right moment. Cells can communicate with each other through direct cell-cell contact or remotely through secretion of soluble signaling molecules. These soluble molecules include secreted proteins that can be recognized by other cells if they express the right receptors.

We developed a library of human secreted proteins for use in several high-throughput screens to identify additional secreted proteins that affect specific immune responses. This approach led to the identification of fibroblast growth factors as a class of viral replication inhibitors, soluble FAS ligand as an inducer of memory B cell differentiation into antibody secreting cells, and IL-21 an inducer of granzyme B expression in activated CD4+ T cells. In addition, the research in this thesis describes that tumor infiltrating lymphocytes (TILs) derived from renal cell carcinoma cannot make sufficient cytokines when co-cultured with autologous tumor digest, a type of secreted proteins, after in vitro expansion.

In conclusion, this thesis revealed additional roles of known secreted proteins that support intercellular communication during immune responses, thereby expanding our knowledge of immunological communication.