--- _id: '14274' abstract: - lang: eng text: Immune responses rely on the rapid and coordinated migration of leukocytes. Whereas it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how these gradients are generated, maintained, and modulated. By combining experimental data with theory on leukocyte chemotaxis guided by the G protein–coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and a modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, dynamically shaping the spatiotemporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, and provide a guidance cue for other comigrating cells. Such a dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization. acknowledgement: "We thank I. de Vries and the Scientific Service Units (Life Sciences, Bioimaging, Nanofabrication, Preclinical and Miba Machine Shop) of the Institute of Science and Technology Austria for excellent support, as well as all the rotation students assisting in the laboratory work (B. Zens, H. Schön, and D. Babic).\r\nThis work was supported by grants from the European Research Council under the European Union’s Horizon 2020 research to M.S. (grant agreement no. 724373) and to E.H. (grant agreement no. 851288), and a grant by the Austrian Science Fund (DK Nanocell W1250-B20) to M.S. J.A. was supported by the Jenny and Antti Wihuri Foundation and Research Council of Finland's Flagship Programme InFLAMES (decision number: 357910). M.C.U. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 754411." article_number: adc9584 article_processing_charge: No article_type: original author: - first_name: Jonna H full_name: Alanko, Jonna H id: 2CC12E8C-F248-11E8-B48F-1D18A9856A87 last_name: Alanko orcid: 0000-0002-7698-3061 - first_name: Mehmet C full_name: Ucar, Mehmet C id: 50B2A802-6007-11E9-A42B-EB23E6697425 last_name: Ucar orcid: 0000-0003-0506-4217 - first_name: Nikola full_name: Canigova, Nikola id: 3795523E-F248-11E8-B48F-1D18A9856A87 last_name: Canigova orcid: 0000-0002-8518-5926 - first_name: Julian A full_name: Stopp, Julian A id: 489E3F00-F248-11E8-B48F-1D18A9856A87 last_name: Stopp - first_name: Jan full_name: Schwarz, Jan id: 346C1EC6-F248-11E8-B48F-1D18A9856A87 last_name: Schwarz - first_name: Jack full_name: Merrin, Jack id: 4515C308-F248-11E8-B48F-1D18A9856A87 last_name: Merrin orcid: 0000-0001-5145-4609 - first_name: Edouard B full_name: Hannezo, Edouard B id: 3A9DB764-F248-11E8-B48F-1D18A9856A87 last_name: Hannezo orcid: 0000-0001-6005-1561 - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 citation: ama: Alanko JH, Ucar MC, Canigova N, et al. CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science Immunology. 2023;8(87). doi:10.1126/sciimmunol.adc9584 apa: Alanko, J. H., Ucar, M. C., Canigova, N., Stopp, J. A., Schwarz, J., Merrin, J., … Sixt, M. K. (2023). CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science Immunology. American Association for the Advancement of Science. https://doi.org/10.1126/sciimmunol.adc9584 chicago: Alanko, Jonna H, Mehmet C Ucar, Nikola Canigova, Julian A Stopp, Jan Schwarz, Jack Merrin, Edouard B Hannezo, and Michael K Sixt. “CCR7 Acts as Both a Sensor and a Sink for CCL19 to Coordinate Collective Leukocyte Migration.” Science Immunology. American Association for the Advancement of Science, 2023. https://doi.org/10.1126/sciimmunol.adc9584. ieee: J. H. Alanko et al., “CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration,” Science Immunology, vol. 8, no. 87. American Association for the Advancement of Science, 2023. ista: Alanko JH, Ucar MC, Canigova N, Stopp JA, Schwarz J, Merrin J, Hannezo EB, Sixt MK. 2023. CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration. Science Immunology. 8(87), adc9584. mla: Alanko, Jonna H., et al. “CCR7 Acts as Both a Sensor and a Sink for CCL19 to Coordinate Collective Leukocyte Migration.” Science Immunology, vol. 8, no. 87, adc9584, American Association for the Advancement of Science, 2023, doi:10.1126/sciimmunol.adc9584. short: J.H. Alanko, M.C. Ucar, N. Canigova, J.A. Stopp, J. Schwarz, J. Merrin, E.B. Hannezo, M.K. Sixt, Science Immunology 8 (2023). date_created: 2023-09-06T08:07:51Z date_published: 2023-09-01T00:00:00Z date_updated: 2023-12-21T14:30:01Z day: '01' department: - _id: MiSi - _id: EdHa - _id: NanoFab doi: 10.1126/sciimmunol.adc9584 ec_funded: 1 external_id: isi: - '001062110600003' pmid: - '37656776' intvolume: ' 8' isi: 1 issue: '87' keyword: - General Medicine - Immunology language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1126/sciimmunol.adc9584 month: '09' oa: 1 oa_version: Published Version pmid: 1 project: - _id: 25FE9508-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '724373' name: Cellular navigation along spatial gradients - _id: 05943252-7A3F-11EA-A408-12923DDC885E call_identifier: H2020 grant_number: '851288' name: Design Principles of Branching Morphogenesis - _id: 265E2996-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W01250-B20 name: Nano-Analytics of Cellular Systems - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships publication: Science Immunology publication_identifier: issn: - 2470-9468 publication_status: published publisher: American Association for the Advancement of Science quality_controlled: '1' related_material: record: - id: '14279' relation: research_data status: public - id: '14697' relation: dissertation_contains status: public scopus_import: '1' status: public title: CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 8 year: '2023' ... --- _id: '6891' abstract: - lang: eng text: "While cells of mesenchymal or epithelial origin perform their effector functions in a purely anchorage dependent manner, cells derived from the hematopoietic lineage are not committed to operate only within a specific niche. Instead, these cells are able to function autonomously of the molecular composition in a broad range of tissue compartments. By this means, cells of the hematopoietic lineage retain the capacity to disseminate into connective tissue and recirculate between organs, building the foundation for essential processes such as tissue regeneration or immune surveillance. \r\nCells of the immune system, specifically leukocytes, are extraordinarily good at performing this task. These cells are able to flexibly shift their mode of migration between an adhesion-mediated and an adhesion-independent manner, instantaneously accommodating for any changes in molecular composition of the external scaffold. The key component driving directed leukocyte migration is the chemokine receptor 7, which guides the cell along gradients of chemokine ligand. Therefore, the physical destination of migrating leukocytes is purely deterministic, i.e. given by global directional cues such as chemokine gradients. \r\nNevertheless, these cells typically reside in three-dimensional scaffolds of inhomogeneous complexity, raising the question whether cells are able to locally discriminate between multiple optional migration routes. Current literature provides evidence that leukocytes, specifically dendritic cells, do indeed probe their surrounding by virtue of multiple explorative protrusions. However, it remains enigmatic how these cells decide which one is the more favorable route to follow and what are the key players involved in performing this task. Due to the heterogeneous environment of most tissues, and the vast adaptability of migrating leukocytes, at this time it is not clear to what extent leukocytes are able to optimize their migratory strategy by adapting their level of adhesiveness. And, given the fact that leukocyte migration is characterized by branched cell shapes in combination with high migration velocities, it is reasonable to assume that these cells require fine tuned shape maintenance mechanisms that tightly coordinate protrusion and adhesion dynamics in a spatiotemporal manner. \r\nTherefore, this study aimed to elucidate how rapidly migrating leukocytes opt for an ideal migratory path while maintaining a continuous cell shape and balancing adhesive forces to efficiently navigate through complex microenvironments. \r\nThe results of this study unraveled a role for the microtubule cytoskeleton in promoting the decision making process during path finding and for the first time point towards a microtubule-mediated function in cell shape maintenance of highly ramified cells such as dendritic cells. Furthermore, we found that migrating low-adhesive leukocytes are able to instantaneously adapt to increased tensile load by engaging adhesion receptors. This response was only occurring tangential to the substrate while adhesive properties in the vertical direction were not increased. As leukocytes are primed for rapid migration velocities, these results demonstrate that leukocyte integrins are able to confer a high level of traction forces parallel to the cell membrane along the direction of migration without wasting energy in gluing the cell to the substrate. \r\nThus, the data in the here presented thesis provide new insights into the pivotal role of cytoskeletal dynamics and the mechanisms of force transduction during leukocyte migration. \r\nThereby the here presented results help to further define fundamental principles underlying leukocyte migration and open up potential therapeutic avenues of clinical relevance.\r\n" alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Aglaja full_name: Kopf, Aglaja id: 31DAC7B6-F248-11E8-B48F-1D18A9856A87 last_name: Kopf orcid: 0000-0002-2187-6656 citation: ama: Kopf A. The implication of cytoskeletal dynamics on leukocyte migration. 2019. doi:10.15479/AT:ISTA:6891 apa: Kopf, A. (2019). The implication of cytoskeletal dynamics on leukocyte migration. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:6891 chicago: Kopf, Aglaja. “The Implication of Cytoskeletal Dynamics on Leukocyte Migration.” Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:6891. ieee: A. Kopf, “The implication of cytoskeletal dynamics on leukocyte migration,” Institute of Science and Technology Austria, 2019. ista: Kopf A. 2019. The implication of cytoskeletal dynamics on leukocyte migration. Institute of Science and Technology Austria. mla: Kopf, Aglaja. The Implication of Cytoskeletal Dynamics on Leukocyte Migration. Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:6891. short: A. Kopf, The Implication of Cytoskeletal Dynamics on Leukocyte Migration, Institute of Science and Technology Austria, 2019. date_created: 2019-09-19T08:19:44Z date_published: 2019-07-24T00:00:00Z date_updated: 2023-10-18T08:49:17Z day: '24' ddc: - '570' degree_awarded: PhD department: - _id: MiSi doi: 10.15479/AT:ISTA:6891 file: - access_level: closed checksum: 00d100d6468e31e583051e0a006b640c content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: akopf date_created: 2019-10-15T05:28:42Z date_updated: 2020-10-17T22:30:03Z embargo_to: open_access file_id: '6950' file_name: Kopf_PhD_Thesis.docx file_size: 74735267 relation: source_file - access_level: open_access checksum: 5d1baa899993ae6ca81aebebe1797000 content_type: application/pdf creator: akopf date_created: 2019-10-15T05:28:47Z date_updated: 2020-10-17T22:30:03Z embargo: 2020-10-16 file_id: '6951' file_name: Kopf_PhD_Thesis1.pdf file_size: 52787224 relation: main_file file_date_updated: 2020-10-17T22:30:03Z has_accepted_license: '1' keyword: - cell biology - immunology - leukocyte - migration - microfluidics language: - iso: eng month: '07' oa: 1 oa_version: Published Version page: '171' project: - _id: 265E2996-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W01250-B20 name: Nano-Analytics of Cellular Systems publication_identifier: eissn: - 2663-337X isbn: - 978-3-99078-002-2 publication_status: published publisher: Institute of Science and Technology Austria related_material: link: - relation: press_release url: https://ist.ac.at/en/news/feeling-like-a-cell/ record: - id: '6328' relation: part_of_dissertation status: public - id: '15' relation: part_of_dissertation status: public - id: '6877' relation: part_of_dissertation status: public status: public supervisor: - first_name: Michael K full_name: Sixt, Michael K id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87 last_name: Sixt orcid: 0000-0002-6620-9179 title: The implication of cytoskeletal dynamics on leukocyte migration type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2019' ...