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Explore a selection of research case studies from the past five years.

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Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

Mouse lymph nodes

New imaging protocol for a deep dive into mouse lymph nodes

Lymph nodes are small organs distributed throughout the body that orchestrate immune processes. In response to infection, vaccination, or cancer, a germinal centre (GC) forms within them, driving the maturation of memory B cells and plasma cells. Because of their 3D structure and diverse cell types, GCs are ideal for 3D imaging. This protocol describes rapid, high-resolution multicolour imaging of whole immunised lymph nodes, covering harvesting, fixation, permeabilisation, staining, and clearing. Imaging is performed with a fluorescence lightsheet microscope, and analysis with Imaris. It quantifies GC B cells, plasma cells, and follicular T cells, and includes optimised stainings for visualising other lymph node structures.

Protocol for rapid 5-plex 3D imaging and single-cell analysis of immune responses in whole murine lymph nodes

Published in STAR Protocols

Published

A spleen tissue cross-section.

Metabolic reprogramming B cells to counteract hypoxia

The germinal centres (GCs) of the body act as factories where antibody-secreting B cells are fine-tuned to reach their highest antigen affinity. GC-B cells cycle between two GC zones, undergoing antigen-driven selection and initiating cell division in the light zone (LZ), before migrating to the dark zone (DZ), where they vigorously proliferate. Initiation of cell division in the LZ was a puzzle, as the low-oxygen conditions in the LZ normally induce cell cycle arrest. Researchers at the Crick showed that a microRNA called miR-155 metabolically reprogrammes LZ GC-B cells by regulating genes that enhance energy production and prevent cell death. This process is essential for effective immune function in the face of infection.

Epi-microRNA mediated metabolic reprogramming counteracts hypoxia to preserve affinity maturation

Published in Nature Communications

Published

B cell selection process

B cell selection process outlined

To mount a robust immune response, immune cells called IgG1 B cells must be selected within the germinal centres of lymphoid organs to produce high affinity antibodies against pathogens. Despite the importance of this process, its mechanism remains largely elusive. By investigating the role of genes in germinal centre B cells, researchers at the Crick revealed that a protein called MIZ1 was critical for the selection of IgG1 B cells and production of high-affinity antibodies. Specifically, MIZ1, a protein known for its role in gene regulation, was identified as a key player in driving the expression of TMBIM4, which ultimately prevented IgG1 B cell death due to excessive calcium signalling, ensuring IgG1 B cell survival during the critical selection process. These findings underscore the significance of MIZ1 and TMBIM4 in shaping the immune response during infection and vaccination.

Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TMBIM4 safeguards IgG1+ GC B cell-positive selection

Published in Science Immunology

Published

Restriction of memory B cell differentiation at the germinal center B cell positive selection stage

Memory B cells (MBCs) are key for protection from reinfection. However, it is mechanistically unclear how germinal center (GC) B cells differentiate into MBCs. MYC is transiently induced in cells fated for GC expansion and plasma cell (PC) formation, so-called positively selected GC B cells. We found that these cells coexpressed MYC and MIZ1 (MYC-interacting zinc-finger protein 1 [ZBTB17]). MYC and MIZ1 are transcriptional activators; however, they form a transcriptional repressor complex that represses MIZ1 target genes. Mice lacking MYC-MIZ1 complexes displayed impaired cell cycle entry of positively selected GC B cells and reduced GC B cell expansion and PC formation. Notably, absence of MYC-MIZ1 complexes in positively selected GC B cells led to a gene expression profile alike that of MBCs and increased MBC differentiation. Thus, at the GC positive selection stage, MYC-MIZ1 complexes are required for effective GC expansion and PC formation and to restrict MBC differentiation. We propose that MYC and MIZ1 form a module that regulates GC B cell fate.

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Published in Journal of Experimental Medicine

Published

Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth

Memory B cells (MBCs) and plasma cells (PCs) are formed during the so-called germinal center (GC) B cell reaction. In the GC reaction B cells mutate their B cell receptor (BCR) genes and those that acquire a higher-affinity BCR for a pathogen antigen are presumably selected to survive and differentiate, whereas B cells carrying a lower-affinity BCR die. However, this cannot explain retention of GC B cells with varied BCR affinities and the formation of MBCs that normally carry lower-affinity BCRs. This work re-defines selection of GC B cells as permissive to ensure clonal diversity and broad protection.

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Published in Proceedings of the National Academy of Sciences of the United States of America

Published

RAC1P29S induces a mesenchymal phenotypic switch via serum response factor to promote melanoma development and therapy resistance

Metastatic melanoma is a lethal disease, in part because of rapid acquisition of resistance to therapy. Using genetically engineered mouse models, we demonstrate that the activating RAC1 P29S mutation, present in up to 5% of melanoma patients, cooperates with BRAF as a driver of melanoma initiation and promotes BRAF inhibitor resistance. The critical RAC1 effector pathway in melanoma is shown to be the transcription factor complex SRF/MRTF, which initiates a switch to a mesenchymal-like state characterized by therapy resistance. Therapeutic targeting of SRF/MRTF may have potential to reverse BRAF inhibitor resistance in melanoma patients bearing the oncogenic RAC1 P29S mutation

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Published in Cancer Cell

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.