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Instruments / Technical Area	Publication Details	Published
B24-Cryo Soft X-ray Tomography	A ‘protein bomb’ used by the immune system to kill infected and cancerous cells Michael Dustin Diamond Proposal Number(s): [23000] Show Abstract ▼ Abstract: Cytotoxic T cells (CTLs) kill infected and cancerous cells by secreting cytotoxic proteins. An international team of researchers investigated how these cytotoxic proteins avoid dilution in the vast extracellular space and enter target cells that need to be killed. The question they were seeking to answer was whether these proteins organise into particles. Diamond Light Source's 3D X-ray tomography and super resolution fluoresence microscopy for the life sciences beamline (B24) uses soft (low-energy) X-rays to generate 3D maps of organic material in cells and small particles released from cells. For this research, B24 provided correlative information about ‘protein bombs’ released by cytotoxic T cells and within the cells. Soft X-rays were better than electrons in this case as they allow imaging of entire T cells, although the resolution is lower. The results allowed the team to confirm that the ‘protein bombs’ had a ‘core-shell’ structure and identify potential storage sites for the ‘protein bombs’ in the T cells. Whereas most biological drugs are single protein molecules, ‘protein bombs’ are ‘supramolecular’, a loose assembly of hundreds or thousands of proteins that deliver the active components to targets in the body. These ‘protein bombs’ have the potential to be used in immunotherapy applications, which help the body’s immune system to fight cancer and other diseases. One of the next steps for the research team is to try to make synthetic ‘protein bombs’. B24 will be helpful in characterising these ‘supramolecular’ drugs.	Jul 2021
B24-Cryo Soft X-ray Tomography	Identification of distinct cytotoxic granules as the origin of supramolecular attack particles in T lymphocytes Hsin-Fang Chang , Claudia Schirra , Momchil Ninov , Ulrike Hahn , Keerthana Ravichandran , Elmar Krause , Ute Becherer , Stefan Balint , Maria Harkiolaki , Henning Urlaub , Salvatore Valitutti , Cosima T. Baldari , Michael L. Dustin , Reinhard Jahn , Jens Rettig Nature Communications 13 DOI: 10.1038/s41467-022-28596-y Open Access Show Abstract ▼ Abstract: Cytotoxic T lymphocytes (CTL) kill malignant and infected cells through the directed release of cytotoxic proteins into the immunological synapse (IS). The cytotoxic protein granzyme B (GzmB) is released in its soluble form or in supramolecular attack particles (SMAP). We utilize synaptobrevin2-mRFP knock-in mice to isolate fusogenic cytotoxic granules in an unbiased manner and visualize them alone or in degranulating CTLs. We identified two classes of fusion-competent granules, single core granules (SCG) and multi core granules (MCG), with different diameter, morphology and protein composition. Functional analyses demonstrate that both classes of granules fuse with the plasma membrane at the IS. SCG fusion releases soluble GzmB. MCGs can be labelled with the SMAP marker thrombospondin-1 and their fusion releases intact SMAPs. We propose that CTLs use SCG fusion to fill the synaptic cleft with active cytotoxic proteins instantly and parallel MCG fusion to deliver latent SMAPs for delayed killing of refractory targets.	Feb 2022
B24-Cryo Soft X-ray Tomography	Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells S. Balint , S. Müller , R. Fischer , B. M. Kessler , M. Harkiolaki , S. Valitutti , M. L. Dustin Science DOI: 10.1126/science.aay9207 Diamond Proposal Number(s): [23000] Show Abstract ▼ Abstract: Cytotoxic T lymphocytes (CTLs) kill infected and cancerous cells. We detected transfer of cytotoxic multiprotein complexes from CTLs to target cells, termed supramolecular attack particles (SMAPs). SMAPs were rapidly released from CTLs and were autonomously cytotoxic. Mass spectrometry, immunochemical analysis and CRISPR editing identified a C-terminal fragment of thrombospondin-1 as an unexpected SMAP component that contributed to target killing. Direct stochastic optical reconstruction microscopy resolved a cytotoxic core surrounded by a thrombospondin-1 shell of ~120 nm diameter. Cryo-soft x-ray tomography analysis revealed that SMAPs had a carbon-dense shell and were stored in multicore granules. We propose that SMAPs are autonomous extracellular killing entities that deliver cytotoxic cargo based on specificity of shell components.	May 2020

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