B cells start developing in the bone marrow and then move
through the spleen, lymph nodes and blood, taking on tasks that range
from recognizing foreign substances to replication, quiescence, and
generating a lasting memory of pathogens. These lymphocytes are best known for making antibodies.
B cells have different metabolic needs depending on their
environment. But little is known about how B
cell metabolism adapts to each of these environments, insights that may
improve our understanding of B cell diseases, such as non-Hodgkin's
‘The protein GSK3 acts as a metabolic sensor, or checkpoint, that promotes the survival of circulating B cells while limiting growth and proliferation of B cells in germinal centers.’
"Our research shows that the protein GSK3 plays a crucial role in
helping B cells meet the energy needs of their distinct states," says
Robert Rickert, director of the Tumor Microenvironment and Cancer
Immunology Program at Sanford Burnham Prebys Medical Discovery
Institute (SBP). "It acts as a metabolic sensor, or checkpoint, that
promotes the survival of circulating B cells while limiting growth and
proliferation of B cells in germinal centers.
The findings are
particularly relevant for certain B cell pathologies, including lymphoma
subtypes, where there is an increased demand for energy to support the
hyperproliferation of cells in a microenvironment that may be limited in
In the blood, circulating B cells are quiescent, consuming
little energy. In germinal centers - the sites within lymph nodes where
mature B cells cluster - B cells proliferate and undergo hypermutation of
their antibody genes to generate high-affinity antibodies. These
processes require enormous amounts of energy, so these B cells consume
lots of sugars, fatty acids and amino acids.
The new study, published today in Nature Immunology
that GSK3 adjusts metabolism to match each of these needs. In
circulating B cells, GSK3 limits overall metabolic activity, while in
proliferating B cells in germinal centers, GSK3 slows glycolysis and
production of mitochondria.
GSK3 function is essential for B cell survival in germinal centers.
To understand why, Rickert's team looked at how B cells in these regions
generate energy, and found that because these B cells are so
metabolically active, they consume nearly all available glucose. That
switches on a secondary, less efficient but non-oxygen-dependent means
of generating energy called glycolysis. High glycolytic activity leads
to accumulation of toxic reactive oxygen species (ROS), as does rapid
manufacture of mitochondria, which tend to leak the same chemicals.
Thus, by restraining metabolism in specific ways, GSK3 prevents
ROS-induced cell death.
"Our results were really surprising," Rickert commented. "Until now,
we would have thought that slowing metabolism would only be important
for preventing B cells from becoming cancerous - which it indeed may be.
These studies provide insight into the dynamic nature of B cell
metabolism that literally 'fuels' differentiation in the germinal center
to produce an effective antibody response"
"It's not yet clear whether or how GSK3 might be a target for future
therapies for B cell-related diseases, but this research opens a lot of
doors for further studies," Rickert said. "To start with, we plan to
investigate how GSK3 is regulated in lymphoma and how that relates to
changes in metabolism. That research could lead to new approaches to