T-cells are having a moment. Well maybe not like Game of Thrones is having a moment, but as stars of the cancer treatment, immunotherapy, T-cells are definitely cool. But what is a T-cell? And how can you get one?
Good news! Your body makes T-cells for you, a lot of them.
All the time.
Wannabe T-cells are born
in bone marrow and migrate to the butterfly-shaped organ called the thymus. Put
your hand on your neck, right where the collar bones meet. There, now you’re
almost touching your thymus, which is in your rib
cage just above your heart. A butterfly is a good metaphor to keep in
mind, too. Like an egg becomes a caterpillar that becomes a pupa which becomes
a butterfly, the T-cell goes through a life cycle to become the powerhouse
protector of the body. As part of that cycle, T-cells in the thymus learn if
they have aptitude for one of two jobs. But the thymus is less job training and
more Hunger Games. The majority never make it out because the body culls any
that aren’t just right.
Red Alert / Chemical
The overall task of a T-cell is to respond to markers, called antigens, left behind by invaders, which stick to cells in our body. T-cells have a port, or receptor, that matches to an antigen. When that happens, the T-cell turns into either a chemical weapon or an alarm bell.
Both are vital, according to Virginia Shapiro, Ph.D., immunologist and co-lead for the immunity platform for Mayo Clinic’s Center for Biomedical Discovery.
“One type of T-cell can recognize that the danger is
coming from inside a cell, as in the case of a virus, and will inject it with a
granule of toxic chemicals. Those are the cytotoxic (kills living cells)
T-cells or CD8 T-cells,” she explains. The other type is the CD4, or
helper T-cell, Dr. Shapiro continues. “These are the cells that get the
immune message, become activated, but do not kill the messenger.”
Sometimes T-cells can take care of the problem then and
there, but other times, the immune system needs to coordinate for a larger
clean-up mission. So both types of T-cells are important for a robust immune
But remember: ALL THE THINGS. How can your body create T-cells
with receptors for all the antigens it might encounter?
“How many protein-coding
genes are there in people?” asks Dr. Shapiro. “Twenty-one thousand-ish,” she says, answering her
own question. “But the body has to make antigen receptors to, well, let’s
just say a gazillion things for simplicity.” She explains that the way
that happens is the body takes gene segments, mixes and matches them in a way
that’s, “actually a bit sloppy but that increases diversity even more.”
And what you get is a T-cell with a receptor but no idea
what it might recognize.
“Two thirds of the rearrangements will produce
junk,” says Dr. Shapiro. “So part of the process is to go through
quality control checkpoints so you only keep T-cells with receptors that are
good.” In the thymus, immature T cells are tested. If the response from
the receptor array (signal) does not react to anything, they’re told to die. If
their receptor reacts to the part of the cell that defines “you” (versus
“not-you”) then they’re also culled to prevent damage to your own
“You need the signal through the receptor to be not too
strong, not too weak but just right,” says Dr. Shapiro. “Once it’s in
that goldilocks zone, the T-cell has a choice. Do I become a helper T-cell or a
Providing a Choice
In a recent paper in eLife, Dr. Shapiro and her team clarified an important part of this process in mice. At the point where surviving T-cells choose what to be, an enzyme called histone deacetylase 3 or HDAC3 helps keep both options open. It is part of a family of enzymes that typically repress gene expression. In this case Dr. Shapiro’s team reports that HDAC3 holds back the expression of genes that push a T-cell to become cytotoxic and allow T-cells down the path of becoming helper cells.
“When it comes to making that decision T-cells have two
fates,” says Dr. Shapiro. “But when HDAC3 is gone, it doesn’t matter
if you were supposed to be a cytotoxic or a helper. The deck is stacked and everybody
That means only T-cell chemical weapons, no T-cell alarms to
coordinate immune response.
In a separate paper, published in The Journal of Immunology, the team expanded on the role of HDAC3. They report that it also suppresses genes for a particular receptor called P2X7.
“P2X7 is a receptor that recognizes the energy molecule
in cells, which they release as they die,” explains Dr. Shapiro.
“With only 10 percent of T-cells in the goldilocks zone, there are lots of
dying cells, meaning the thymus is an environment rich in that molecule, called
ATP. So without HDAC3, you have more P2X7 receptor
expressed on the surface of the T-cells and more cell death, meaning fewer
T-cells in general.”
That means without HDAC3, the body can only produce chemical
weapons and will produce fewer T-cells in general.
And that could be a problem for patients during cancer
Informs Cancer Therapies
Some cancer treatments use HDAC-inhibitors. That is, as part
of treatment they block HDAC. Now, if you already have helper T-cells you don’t
“But tumors are really good at shutting down an immune
response and exhausting T-cells,” says Dr. Shapiro. “You depend on
having newly generated T-cells coming into the tumor that have not been spoiled
by the tumor. So these inhibitors may have an effect on normal cells and
introduce unintended effects.”
Right now, Dr. Shapiro says, we have the broad picture and
we know HDAC3 is critical, but “the next step is to understand it at a
mechanistic level and ask the molecular questions.”
To improve cancer therapy, we have to understand one of the
body’s best weapons against it, says Dr. Shapiro.
“If you have diseases which disrupt the ability to make
T-cells it has a severe effect on health,” Dr. Shapiro says. “So at the
most basic level we care about how you make a T-cell.”