Biophysical basis of single cell force spectroscopy

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Historically, immunological research has been a protein-centric endeavor, with signaling events often defined as biochemical changes of polypeptides. How biophysical factors play into this scheme has been mostly overlooked. Funded by our last NSERC support, we have used atomic force microscopy (AFM)-based single cell force spectroscopy (SCFS) to elucidate several important immunological events that are driven by biophysical changes at the cell membrane. We have found that particulate substances ligate surface lipid moieties with substantial intensity, causing rearrangement of the bilayer membrane. This lipid sorting aggregates signaling molecules and triggers phagocytosis and dendritic cell activation. Our previous work therefore introduces the concept of force and physical disturbance into the realm of immune activation. In this proposal, we substantially move this concept forward and suggest that the immune system is constantly under the regulation of biophysical factors. We provide evidence that regulatory T cells, a group of CD4+ T cells essential to control autoimmunity, bind strongly to dendritic cells and suppress the latter’s ability to mount unwanted immune activation. We also show that peripheral lymphoid volume or the number of total immune cells in the system is regulated by steady state interaction between T cells and dendritic cells. Namely the physical binding between these two cell types provides a trickling signal to control the expansion and contraction of immune cells. We propose to use AFM and photonic force microscopy to further study the essential parameters of these interactions and signaling events associated with these biophysical changes. The outcomes of this work will open a new page in immunological research, and introduce biophysics as an essential aspect of immune regulation. Because the topic of research is of great importance in public health and technologies used to carry the work are in line with the central mission of NSERC, we believe that the investment here will be highly rewarding in years to come.