When the body is fighting an invading pathogen, white blood cells, including T cells, must respond. T-cell receptors (TCRs) recognize pathogens during T-cell–mediated adaptive immune responses. The binding between TCRs and antigen peptides is of relatively low affinity and is degenerate, in that, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR. Therefore, the more TCRs are characterized, the more important information will be revealed regarding T cell responses, including anti-tumour defences. Now, a study from researchers at Salk Institute images how vital receptors on the surface of T cells bundle together when activated. The team state that their study is the first to visualize this process in lymph nodes and could help scientists better understand how to turn-up or down the immune system’s activity to treat autoimmune diseases, infections or even cancer. The study is published in the journal Proceedings of the National Academy of Sciences.
Previous studies show that T cells are activated when receptors, known as TCRs, embedded in their outer membrane bind to other immune cells that have digested an antigen, such as a virus, bacteria or cancer cell. In turn, the activated T cells switch on cellular pathways that help the body both actively seek out and destroy the antigen and remember it for the future. T-cell activation critically relies on the spatiotemporal arrangements of TCRs on the plasma membrane. In the past, by looking at TCRs embedded in isolated cells under the microscope, researchers discovered that the receptors are arranged in clusters, called protein islands, that merge when the cells are activated. However, the molecular organizations of TCRs on lymph node-resident T cells have not yet been determined, owing to the diffraction limit of light. The current study investigates how the receptors are naturally arranged in lymph nodes and how that arrangement might change when the T cells are activated in living hosts.
The current study developed a super-resolution microscope, called light-sheet direct stochastic optical reconstruction microscopy (dSTORM), to watch T cell receptors in the membranes of T cells in mouse lymph nodes. Results validated the previous observation that protein islands of TCRs merge into larger ‘microclusters’ when T cells are activated. Data findings also show that, before cells are activated, the protein islands are already arranged in groups dubbed ‘territories’; the pre-organization on the molecular level basically turns the T cell into a loaded gun.
Results show that TCRs were preclustered into nanometer-scale protein islands, which were organized into larger membrane territories, and that T-cell activation induced the formation of microclusters. The lab state that their data provides the first evidence, to their knowledge, of subdiffraction membrane organizations during immune responses in an animal model system.
The team surmise that understanding how the molecular organization mediates the sensitivity of T cell responses could help the global medical community make the immune system more or less sensitive. For the future, the researchers state that it is hoped in the case of autoimmune diseases, clinicians could turn down the immune system’s activity, and turn up the activity to help fight infections or cancers.
Source: Salk Institute