'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.