The long and short of it

The motor protein KIF21B allows immune cells to keep the microtubules that form their internal scaffolding short as they prepare to defend the body from infection.
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Microtubules (green) and actin (a protein that is part of the cytoskeleton, the scaffold that helps the cell keep its shape, magenta) at the immunological synapse in a type of T cell called a Jurkat cell. Image credit: Hugo G.J. Damstra (CC BY 4.0)

The immune system is composed of many types of cells that can recognize foreign molecules and pathogens so they can eliminate them. When cells in the body become infected with a pathogen, they can process the pathogen’s proteins and present them on their own surface. Specialized immune cells can then recognize infected cells and interact with them, forming an ‘immunological synapse’. These synapses play an important role in immune response: they activate the immune system and allow it to kill harmful cells.

To form an immunological synapse, an immune cell must reorganize its internal contents, including an aster-shaped scaffold made of tiny protein tubes called microtubules. The center of this scaffold moves towards the immunological synapse as it forms. This re-orientation of the microtubules towards the immunological synapse is known as 'polarization' and it happens very rapidly, but it is not yet clear how it works.

One molecule involved in the polarization process is called KIF21B, a protein that can walk along microtubules, building up at the ends and affecting their growth. Whether KIF21B makes microtubules grow more quickly, or more slowly, is a matter of debate, and the impact microtubule length has on immunological synapse formation is unknown.

Here, Hooikaas, Damstra et al. deleted the gene for KIF21B from human immune cells called T cells to find out how it affected their ability to form an immunological synapse. Without KIF21B, the T cells grew microtubules that were longer than normal, and had trouble forming immunological synapses. When the T cells were treated with a drug that stops microtubule growth, their ability to form immunological synapses was restored, suggesting a role for KIF21B. To explore this further, Hooikaas, Damstra et al. replaced the missing KIF21B gene with a gene that coded for a version of the protein that could be seen using microscopy. This revealed that, when KIF21B reaches the ends of microtubules, it stops their growth and triggers their disassembly. Computational modelling showed that cells find it hard to reorient their microtubule scaffolding when the individual tubes are too long. It only takes a small number of KIF21B molecules to shorten the microtubules enough to allow the center of the scaffold to move.

Research has linked the KIF21B gene to autoimmune conditions like multiple sclerosis. Microtubules also play an important role in cell division, a critical process driving all types of cancer. Drugs that affect microtubule growth are already available, and a deeper understanding of KIF21B and microtubule regulation in immune cells could help to improve treatments in the future.