DNA-based microscale Molecular Tension Probe (MTP, firstly introduced in Nature methods 9.1 (2012)) empowers the exploration of pico-Newton (pN) forces exerted by immune cells on their immune receptors, which regulate their immunological ligation. These DNA-based hairpin probes unfold under force application, emitting a fluorescent signal, thus allowing us to measure 'endogenously generated force' by immune cells themselves through a specific receptor-ligand interaction.

Tension Gauge Tether (TGT, firstly introduced in Science 340.6135 (2013)), similar to Microscale Tension Probe (MTP), employs double-stranded (ds) DNA oligos that dissociate above a tunable force threshold. However, TGT differs as it uses dsDNA with open ends, leading to irreversible rupture under forces above the threshold. Thus, we can cap the force magnitude exerted by immune cells on individual immune receptors, resulting in the impact on immune cell spreading on specific ligation and signaling.

For investigating mechanobiology, we are always open to developing novel techniques, allowing us to measure molecular and cellular interactions at the single-molecule or single-cell level. Newly developed techniques will help us to measure force-induced biological functions in a highly efficient and scalable manner.

The human immune system, with its adaptive immunity, wants to efficiently respond to antigens, primarily orchestrated by T cells. T cell activation begins with T cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC) on antigen-presenting cells (APCs). Recent studies using force spectroscopy reveal that TCR-pMHC interactions vary based on antigen type, with agonist antigens exhibiting a catch-bond and antagonist antigens displaying a slip-bond (and Co-receptors CD4/8 influence these interactions). T cells, binding to agonist antigens, generate endogenous forces, correlating precisely with TCR signaling. In essence, T cell mechanobiology involves nuanced interactions influenced by antigens, co-receptors, and endogenous forces, intricately connected to TCR signaling. Let's use these findings towards therapeutic application!

Humoral immunity involves the action of B cells. Upon encountering antigens, B cells differentiate into plasma/memory cells, producing antibodies that circulate in bodily fluids. These antibodies play a crucial role in neutralizing pathogens and enhancing the immune response against infections. Investigating B cell mechanobiology entails examining how mechanical forces affect interactions between receptors and ligands, signal transduction pathways, and the broader responses of B cells. For instance, during the encounter of B cells with antigens, mechanobiological elements contribute to crucial processes such as antigen recognition, antigen endocytosis (or trogocytic), receptor activation, and the subsequent orchestration of immune responses. Lots of immune receptors in B cell (including BCR and CD40), which have been not studied biophysically well, are waiting for us!