Publication highlights

Researchers at the Crick investigated whether dendritic cells detect dead cancer cells via a receptor called DNGR-1, which detects F-actin. Looking at mice with and without the DNGR-1 receptor that had been exposed to carcinogens, they found that mice without DNGR-1 developed tumours significantly earlier and to a greater extent. Next, the team examined whether certain cancer mutations were more likely to be found in the tumours of mice without DNGR-1. They reported an increase in mutations in proteins that bind to the F-actin scaffold. This may be because, in mice with DNGR-1, mutations in these proteins are highlighted as a red flag for the immune system. Without DNGR-1, there's less evolutionary pressure for cancer cells to get rid of them.

A subset of dendritic cells, type 1 conventional dendritic cells (cDC1s), plays a key role in recognising material from dead or damaged cells and showing fragments of that material to killer T cells in a process known as cross-presentation. This is critical for defence against some viruses and cancer. This study uncovers how one cDC1 receptor, DNGR-1, promotes cross-presentation of antigens from dead cells while keeping the cell otherwise 'quiet'. The team discovered that this behaviour depends on a single amino acid within the receptor. Changing this amino acid switches DNGR-1 into an activating receptor, but at the cost of losing cross-presentation efficiency. The findings reveal that DNGR-1 has evolved to prioritise information gathering from dead cells over full immune activation, helping the body learn from self-damage without triggering harmful inflammation.

An effective response to infection is critically dependent on the maturation and proliferation of infection-fighting killer CD8+ T cells. This requires the cytokine IL-2, but how IL-2 is delivered to maturing CD8+ cells has been poorly understood. The Signalling and Transcription Laboratory Laboratory at the Crick has now shown that the transcription factor SRF plays a crucial role in the process. SRF was first discovered as a regulator of genes associated with cell proliferation, but somewhat unexpectedly, its role in CD8+ T cell proliferation is to help in the assembly of cell clusters. This activity requires SRF's MRTF cofactors, which control multiple cytoskeletal structural and regulatory genes. Cell clustering allows IL-2 to be efficiently trafficked between cells, and without it sustained proliferation of CD8+ T cells cannot occur. This work demonstrates a novel way by which SRF can promote cell proliferation.

Dendritic cells are a family of white blood cells that plays a key role in starting the immune response to infection and cancer, as well as vaccination. However, it has been unclear just how many members of the family there are, especially as they can sometimes appear under different guises. Painstaking reconstruction of dendritic cell family trees by the Reis e Sousa lab now shows that there are three basic types of conventional dendritic cells in mice. They are called cDC1, cDC2A and cDC2B and develop in the bone marrow from “baby” dendritic cells that already have decided to become one or the other type. These cDC1, cDC2A and cDC2B precursor cells then leave the bone marrow to grow up in all tissues of the body, where they then act as lookouts to sound the alarm upon detecting infection or cancer development. Equivalent cells are also found in humans, arguing that this is a conserved feature of the dendritic cell family across species. The research clarifies the complexity of the dendritic cell system, opening the door for future studies to study the exact functions of cDC1s, cDC2As and cDC2Bs in the immune system.