cells are long-lived B cells that reside in the bone marrow and churn
out antibodies against previously encountered vaccines or pathogens. While plasma cells are vital components of the immune system, they
can also be a contributor to disease, as is the case in autoimmune
diseases, such as lupus and rheumatoid arthritis, and in certain
cancers, such as multiple myeloma.
Now, a group led by researchers at the University of Pennsylvania
School of Veterinary Medicine, has come to a better understanding of how
these cells are maintained. Using a specialized type of microscope that
captures the movement and interaction of cells in living organisms, the
scientists observed that, in the bone marrow, immune cells called
regulatory T cells closely interact with plasma cells and support them.
When the T cells aren't there, plasma cells vanish.
‘In the bone marrow, immune cells called regulatory T cells closely interact with plasma cells and support them. When the T cells aren't there, plasma cells vanish.’
"This interaction was completely unanticipated," said senior author
Christopher A. Hunter, Mindy Halikman Heyer Distinguished Professor of
Pathobiology and chair of the Department of Pathobiology at Penn Vet.
"If we can understand what controls these long-lived plasma cells, then
maybe we can augment that interaction, making more plasma cells to, for
example, enhance vaccine efficiency. Or, if you want to limit
autoimmunity or cancer, maybe there is an opportunity to disrupt this
niche to mitigate some of those conditions."
The research, published in the journal Cell Reports
led by two trainees in Hunter's laboratory, Arielle Glatman Zaretsky and
Christoph Konradt, along with a team of researchers from Penn Vet,
Penn's Perelman School of Medicine, Harvard Medical School, Osaka
University, Medimmune, the University of California, San Diego, and The
Hunter's laboratory has long investigated how the immune system
responds to infection with the parasite Toxoplasma gondii. They have
used high-tech microscopy to visualize the dynamics of immune cells and
other structures in living organisms.
This specialized imaging was able to turn up a surprising finding. A
video of the bone marrow in a mouse exposed to T. gondii revealed that
the animal's plasma cells disappeared, later returning as the infection
A few other groups had seen plasma cells behave similarly in
response to systemic inflammation or infection, but the reason for the
drop in plasma cells remained unclear.
"We don't know whether these cells leave the bone marrow or die
there during infection, but, either way, they are gone," said Glatman
Zaretzky. "And that set up a great system to understand what kinds of
cellular interactions normally create the hospitable environment and
allow the plasma cells to remain there."
The research team had noticed that regulatory T cells, which Hunter
calls "the health and safety inspectors" of the immune system because
they keep immune responses at the appropriate level, were located in a
similar region of the bone marrow as the plasma cells, next to the blood
vessels. And, when mice were exposed to an infection, these "T regs"
declined precipitously, just as the plasma cells had.
Together, these observations called to mind an earlier finding by
another group of scientists that showed that T regs play a key role in
protecting the bone marrow from inflammation. In other words, it
suggested that T regs make the bone marrow an immune-privileged site,
shielding its vital components from the potentially damaging effects of
infection or immune response.
Curious whether these T regs interacted with plasma cells, the
researchers examined both cell types in mice that have T regs labeled
with a green fluorescent marker and plasma cells labeled with a yellow
one. They found that T regs appeared to be closely interacting with
plasma cells for extended periods of time.
"No one had put these two cell types together before," Hunter said.
"Yet, when we looked, we saw that these interactions were not rare but
were frequent and sustained."
Further studies found that both of these cell types also interact
with dendritic cells, which are thought to promote plasma-cell survival.
The researchers also demonstrated that T regs were necessary to
maintain plasma cells, showing that enhancing T reg survival in mice
during infection increased plasma-cell numbers and that experimentally
depleting T regs led to reductions in plasma cells.
The work gives insight into how the body is able to sustain plasma
cells for so long, ensuring that they will jump into action even years
after a vaccine was administered or an earlier infection was conquered.
They also lay the foundation for targeting this cell population - a
feat that has thus far escaped scientists - to ameliorate autoimmune
diseases that arise due to inappropriate antibody production or to treat
cancers that form from plasma cells.