Principles of early T-cell activation.

T cells decide whether to attack or stand down based on a single molecular handshake—the binding of a receptor to a fragment of foreign protein—but after 25 years, immunologists still cannot agree on how that handshake triggers the cell to act. This matters because the T-cell receptor (TCR) is the master switch of the adaptive immune system. Without knowing exactly how ligand binding leads to receptor phosphorylation—the first chemical step in activation—researchers are designing immunotherapies partly in the dark. Four competing theories exist: that the receptor changes shape, that pairs of receptors cluster together, that signalling proteins spontaneously reorganise near the contact point, or some combination of all three. The team will use super-resolution fluorescence microscopy to watch these events unfold at cellular contacts in real time. They will test whether signalling proteins reorganise on their own, whether the TCR forms clusters or changes shape, and then build a systems-level model of how these events produce specific signalling outcomes. This is fundamental science with no immediate clinical application. But the same conceptual framework they develop for the TCR could apply to other leukocyte receptors, and they plan to test it directly by designing novel antibody-based immunotherapies. Past work on receptor triggering has already underpinned drugs that reprogram immune cells to attack tumours.