Every time our body encounters a new disease-causing agent, a crucial defence system called adaptive immunity comes into play. T cells, the top agents in this system, survey the internal environment of infected cells and start eliminating the pathogen. T cells are extremely dynamic, capable of changing their structure and makeup when making contact with other cells.
When naive T cells come into contact with an Antigen Presenting Cell (APC) – a host cell that carries antigens (proteins) from the pathogen – a specialised interface known as the immunological synapse is formed between the APC and T cell receptors (TCRs). "The first few minutes of this contact are extremely important … they change the T cell forever," explains Sudha Kumari, Assistant Professor at the Department of Microbiology and Cell Biology (MCB), IISc.
Kumari's team, in collaboration with faculty member Sumantra Sarkar's team from the Department of Physics, has shed new light on this process. Their study in EMBO Reports describes novel cytoskeletal dynamics that shape this contact.
Previous microscopy studies showed that antigen-engaged TCRs rapidly form microclusters at the immunological synapse. Based on conventional imaging, scientists largely assumed that these TCRs are pulled towards the synapse centre so that the receptors can be engulfed into the cell (a process called endocytosis) and contact with the APC can be cut off. This transport is driven by the retrograde (backward) flow of actin – a cytoskeletal protein that forms filaments to shape the cell – from the cell periphery to the centre.
However, T cells can bind to many APCs in succession, which would be impossible if all TCRs were internalised and had to be newly synthesised each time. To investigate this further, the IISc team used high spatial and temporal resolution imaging techniques to track how the TCR microclusters form and move during contact between a T cell and an APC-like lipid bilayer surface. A tracking algorithm was then developed to capture the movement of the microclusters. Surprisingly, nearly 40% of TCR microclusters drifted away from the synapse centre, towards the cell periphery, which cannot be explained by actin retrograde flow alone.
What the team realised was that something else was happening. Actin was forming wavefronts (ripples) around the synapse centre propagating outward towards the cell edge. The motion of these waves was tightly linked to the outward movement of TCR microclusters. The team also found that naive T cells lacking a key protein linked to immunodeficiency disorders called WASP showed a clear decoupling between actin waves and TCR motion.
The study shows how the actin wavefronts actively transport nearly half of the TCRs away from the synapse centre, and rescue them from endocytosis. This is paradoxical because actin typically moves in a reverse direction in cells. "It's like saying the river flows both ways. How do you even imagine that?" says Kumari.
Samuel Khiangtze, PhD student in the Department of Physics and one of the first authors, says that the findings also point to a broader theoretical gap in biophysics. "The remarkable patterns observed in the experiment raise a lot of interesting questions about the underlying physics of active cytoskeleton and motivate us to investigate the role of activity in the context of dynamic pattern formation," he says.
For Aheria Dey, PhD student at MCB and another first author, the implications are deeply immunological. The immune synapse, she explains, is the "decision-making point" that determines whether a T cell responds appropriately, and subtle cytoskeletal dynamics – often overlooked – may tip that balance. Deep knowledge of this aspect would greatly inform research in cancer therapy and autoimmune diseases.
