Clustered centrosomes help dendritic cells to stabilize their locomotion along chemotactic cues
A migration mechanism previously known only from metastatic cancer cells has now also been demonstrated for leukocytes. This is the conclusion of a recent study led by researchers from ImmunoSensation2 at the University of Bonn. According to the study, centrioles of dendritic cells proliferate and cluster together. This makes it easier for the cells to maintain their direction and thus migrate more quickly to the lymph nodes, where they activate other immune cells. The results have now been published in the Journal of Cell Biology.
Upon antigen recognition, dendritic cells move to a nearby lymphatic vessel through which they travel to a draining lymph node. Here, they activate T-cells to fight the respective pathogen identified. To evoke this reaction as soon as possible, dendritic cells are required to make it to a lymph node quickly. "We have discovered a mechanism that helps them doing this," explains Prof. Dr. Eva Kiermaier from the LIMES Institute (Life and Medical Sciences) at the University of Bonn. "To do so, they form more of certain structures called centrosomes. These help them maintain their direction for longer and thus reach the lymphatic vessels more quickly."
Centrosomes not only important in cell division
In proliferating cells, the number of centrosomes is strictly regulated and generally limited to one. Only prior to mitosis, there are two centrosomes which migrate to opposite poles of the cell, stretching a bundle of microtubules between them. Thereby, they pull the chromosomes apart during cell division. Each of the resulting daughter cells thus receives a complete set of genetic material as well as one of the two centrosomes.
"However, centrosomes are also responsible for organizing the cytoskeleton during cell migration," emphasizes Eva Kiermaier, Professor at the LIMES Institute at Bonn University and member of the Cluster of Excellence ImmunoSensation2. “We have now been able to show that dendritic cells form multiple centrosomes as soon as they come into contact with an antigen," says Ann-Kathrin Weier, PhD student at the LIMES Institute and shared first author of the publication together with her colleague Mirka Homrich. The researchers could show that, after dendritic cells recognize an antigen, they undergo incomplete mitosis and arrest in the subsequent G1 phase, resulting in tetraploid cells with accumulated centrosomes. During cell migration, the centrosomes closely cluster together. They then act as functional microtubule organization centers by which they enable an enhanced, sustained locomotion along gradients of chemotactic signals. Strikingly, dendritic cells with additional centrosomes where also found to exhibit increased secretion of inflammatory cytokines and optimized T cell responses.
Staying the course longer to reach the destination more quickly
Dendritic cells have a problem: they do not know where the next lymphatic vessel is via which they can reach the lymph node. In their search, they proceed according to the strategy of "trial and error": they run in one direction for a short while and then change it if they have not encountered a vessel in the process. "The more centrosomes they have, the longer they stay on course before continuing to search in a different direction," says Mirka Homrich. "We were able to show in computer simulations that this allows them to find the lymphatic vessels much faster than they normally would." In the process, the proliferation of centrosomes adjusts their staying power just right - so they don't stick too stubbornly to their direction. This would increase the risk of them going astray and getting completely lost.
The mechanism identified in the study was previously completely unknown in healthy cells. Cancer cells were assumed to use it to form metastases. However, the multiplied centrosomes must not be freely distributed inside the cells. Otherwise, they would severely disrupt functions such as cell division. In both tumor and dendritic cells, the organelles therefore congregate at a single site - they cluster. "There are now agents that disrupt this clustering of centrosomes," says Kiermaier, who was brought to the Rhine from Lower Austria (IST Austria, Klosterneuburg) in 2017 through the returnee program of the state of North Rhine-Westphalia. "As a result, the cancer cells can no longer divide correctly, but die."
However, it is also possible that these substances interfere with the immune system - after all, the centrosomes cluster there as well. "We've tested several of these agents in cell cultures," she says. "We've actually found evidence that they could significantly impair the effectiveness of the immune defense." If that will be confirmed in clinical trials, it would be bad news as there could be considerable side effects if the active substances were used in cancer therapy.
Participating institutions
In addition to the University of Bonn, the Charles University in Vestec, Czech Republic, and the Institutes of Science and Technology in Austria and Spain were involved in the work.
Funding
The study was funded by the German Research Foundation (DFG), the Ministry for Innovation, Science and Research NRW, the Chan- Zuckerberg Initiative (USA) and the Czech Research Foundation.
Publication
Ann-Kathrin Weier*, Mirka Homrich*, Stephanie Ebbinghaus, Pavel Juda, Eliška Miková, Robert Hauschild, Lili Zhang, Thomas Quast, Elvira Mass, Andreas Schlitzer, Waldemar Kolanus, Sven Burgdorf, Oliver J. Gruß, Miroslav Hons, Stefan Wieser, Eva Kiermaier; Multiple centrosomes enhance migration and immune cell effector functions of mature dendritic cells. J Cell Biol, 2022; https://doi.org/10.1083/jcb.202107134
Contact
Immunology and Tumor Biology
LIMES Institute of the University of Bonn
Phone: +49 228/73-62819
Email: eva.kiermaier@uni-bonn.de
