Publication highlights

Researchers at the Crick, University of Cambridge, Sanquin and the NOVA University investigated how T cells switch off immune functions as quickly as they are switched on, looking at two mRNA shutdown signals: AU-rich elements (long stretches of nucleotides that signal to other proteins to degrade the mRNA) and m6a methylation (adding chemical red flags to mRNAs to mark them for removal). They mapped all m6a methylation sites in human T cells before and after activation, observing that m6a methylation doesn't happen randomly, but often takes place near AU-rich elements. When these two signals occurred close together, the mRNA rapidly degraded, referred to as 'meta-unstable'. This system allows the immune system to keep the balance between under and overactivation.

COVID-19 restrictions including social distancing were lifted in the UK in 2021 after the majority of the population had two doses of vaccine. Researchers at the Crick analysed data from the Legacy study to find out if either infection or vaccine as a third exposure generated different immunity. We found overall that both antibody-mediated and cellular immunity was similar, but when T cells were exposed to spike protein challenge in vitro, infection exposure drove production of more innate immune cytokines from T cells and expansion of mucosal-homing T cells, whereas vaccine-only exposed cells led to expansion of the T cell memory population that produced more inflammatory cytokines.

Researchers at the Crick and Australian National University have shown how two proteins, TCF1 and LEF1, previously only studied in T cells, enable B-1 cells (a type of innate B cell which remains uncharacterised in humans) to apply the brakes on inflammation in mice and used this information to identify signs of B-1 activity in humans. They found that removing TCF1 and LEF1 in adult mice led to the production of a smaller number of dysfunctional B-1a cells that failed to restrain an immune assault on the brain resembling multiple sclerosis. Cells without TCF1 and LEF1 also produced significantly less of an anti-inflammatory compound, IL-10. Finally, the team analysed pleural fluid from people with pleural infections, finding an abundance of B-1-like cells which expressed both genes, as did malignant B cells in people with chronic lymphocytic leukaemia. They also conclude that TCF1 and LEF1 could be harnessed to increase the effectiveness of other immune cells.

Type 2 immunity is central to parasite protection but when dysregulated causes allergy and atopy (tendency to produce an immune response to allergens), and influences neuroprotection, ageing and cancer. Researchers at the Crick have discovered two new ways the receptor for the type 2 cytokines IL-4 and IL-13 (called IL-13Ra1) is modulated. One is sex-specific – female hormones repress expression of this common receptor so that female cells are less responsive. The other is through an ancient retrovirus that integrated near the IL-13Ra1 gene of our primate ancestors, which produces a partially defective IL-13Ra1 that can block the traditional version from signalling. This is a fascinating example where an ancient retroviral infection has affected modern human immunity.

Toxoplasma is a single-cell parasite that infects any warm-blooded animal. It can persist for a long time in the host as it can withstand pathogen-clearing mechanisms. How the parasite circumvents clearance in a wide host range, with different immune mechanisms, remains unknown. To prevent being killed, the parasite secretes ~250 proteins into the host cell. Which of these effector proteins enable infection of all species, and in parasite strains that are particularly virulent in humans, has not been established. Researchers at the Crick and GIMM identified a core set of proteins required for survival in different mouse species with varying susceptibility to Toxoplasma infection. Deletion of the top hit, a protein called GRA12, led to increased host-cell death and early exit of the parasite from the infected cell. The team propose that instead of one virulence factor required across all species, the parasite evolved a suite of effector proteins to counter unique clearance mechanisms in different hosts.

Researchers at the Crick previously discovered that the tail of Influenza virus M2 (matrix 2) protein binds directly to the autophagy (self-eating) protein LC3, which becomes attached to membranes following collapse of pH gradients during infection. In this paper, the team describes a crystal structure of the M2 tail bound to LC3, and report that an unstructured region directly upstream of the interaction is a caspase cleavage motif. Caspases are proteases which can cleave cellular proteins during cell death. In this case, the paper shows that caspase cleavage of M2 disrupts the interaction between M2 and LC3. Functionally, this affects M2 transport to the plasma membrane for virion budding, also disrupts influenza from forming long filaments at the cell surface. This is speculated to be a mechanism to change the structure of virions during cell death, to one that does not require as many cellular resources.

Researchers at the Crick, the UCL Cancer Institute and UCLH have shown that a test called ORACLE can predict lung cancer survival at the point of diagnosis better than currently used clinical risk factors. This could help doctors make more informed treatment decisions for people with stage 1 lung cancer, potentially reducing the risk of the cancer returning or spreading. ORACLE was developed in 2019 to overcome the lack of biological markers in lung cancer, which is important for people with stage 1 lung cancer, who are normally given surgery without chemotherapy. In this study ORACLE was validated in 158 people with lung cancer in the Cancer Research UK-funded TRACERx study. The team found that ORACLE could predict which patients with stage 1 lung cancer had a lower chance of survival, and might benefit from chemotherapy as well as surgery. The researchers also found that high ORACLE risk scores were linked to regions of the tumour that were more likely to spread to another part of the body.

Researchers at the Francis Crick Institute and UCL, funded by Cancer Research UK, have unveiled the first computer algorithm capable of identifying which cell populations within a tumour drive aggressive growth. The innovative algorithm, called SPRINTER, analyses individual cells within a tumour to identify those that are growing the most rapidly. The algorithm was used to analyse nearly 15,000 cancer cells from a patient with non-small cell lung cancer (in TRACERx and PEACE studies). SPRINTER revealed that the cells that were growing the fastest were responsible for spreading the cancer to other parts of the body, even from other metasasised tumours. It also showed that these cells shed more of their DNA into the bloodstream. The possibility of detecting aggressive cancer cell populations early and monitoring them over time offers a new avenue for more proactive and personalised cancer care.