Force spectroscopy in immunological studies

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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 grant, 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 solid substances engage surface lipids with substantial intensity, causing rearrangement of the bilayer membrane. This lipid sorting recruits 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. 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. In addition, we have found that phagocytosis can be initiated via a receptor independent, membrane lipid originated signaling, serving as a generic platform for solid particle uptake. We propose to use AFM coupled to imaging instrument 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. The proposed work will help us understand several fundamental aspects of membrane biology and how cell membrane lipids impact immune signal transduction. This will further lead to our better control of immune cell activation that is at the centre of population health in Canada.