'Helper' T cells, also called CD4 T cells, play a crucial role in coordinating all the different cells in our complex immune systems. Their most well-known task is helping B cells make the antibodies needed to protect us from infection.
But occasionally they act as 'killer' cells, tracking down and killing B cells that are hiding a fugitive such as a virus or are growing out of control, such as B cell lymphomas.
Scientists have now discovered just how CD4 T cells switch to this killer role - a difficult task due to the fact that killer CD4 T cells can be hard to identify.
George Kassiotis of the Francis Crick Institute led the research. He explains: "T cells expressing the CD4 glycoprotein play a crucial role in the immune response. This is disastrously evident in people with AIDS, where CD4 T cells are destroyed by the HIV retrovirus, resulting in a complete collapse of the immune system.
"The best known role of CD4 T cells is helping B cells make antibodies, but in rare cases they can instead become killer cells. However, how CD4 T cells decide whether to help or kill a B cells was not previously understood."
In the absence of a molecular marker that distinguishes killer CD4 T cells from their helper function, the scientists looked at the transcription of every gene in many individual CD4 T cells. This allowed them to identify the set of genes that program the killer activity.
They were able to show in mouse models that CD4 T cells became helper or killer depending on the type of virus they have to fight.
Image: B cells and immune system checkpoints can influence whether CD4 T cells become helpers or killers.
Infection with retroviruses, the family HIV belongs to, instructs them to become helpers. In contrast, infection with adenoviruses, which cause the common cold and other illnesses in children, instructs them to become killers.
Dr Kassiotis says: "CD4 T cells seem to use a molecular switch to decide whether to become a helper or a killer and these two states are mutually exclusive. But they don't make this decision alone. B cells have a strong influence on CD4 T cells, swaying them to the helper type and away from a killer type. This is something viruses exploit. If a virus infects B cells, it hinders the development of killer CD4 T cells.
"Interestingly, killer CD4 T cell development is controlled by the same immune checkpoints that typically provide immunity to tumours. Blocking such immune checkpoints has recently transformed cancer immunotherapy. We've known for nearly two decades that B cells prevent T cell-mediated immunity to tumours. This work suggests new ways of reversing this effect, which may help in the hunt for new cancer treatments."
The paper, Opposing development of cytotoxic and follicular helper CD4 T cells controlled by the TCF-1-Bcl6 nexus, is published in Cell Reports.