A cellular proliferation,
differentiation or survival require fine-tuned metabolic processes
(oxidation, glycolysis, etc). Autophagy is a metabolic process that
supplies energy trough recycling of cellular byproducts, kind of
cellular green technology. Some type of cells, like neurons which are
exceptionally long-lived, are critically dependent on autophagy.
Immune system also have
few cell types that are exceptionally long-lived, like memory B cells
or plasma cells. They are responsible for protection against
re-infection, the basis for immunity. However, how memory B cells or
plasma cells are able to survive so long (years, or even decades) is
unknown.
Here, new paper
published in Nature Medicine may provide some clues to this
questions. The authors, Min Chen et al., examined the role of
autophagy in memory B cell maintenance (1). I find their research to
be of quite good quality with minimal deficiencies discussed below.
First, the authors
showed that unlike germinal center B cells, sorted memory B cells are
resistant to spontaneous cell death in an in vitro culture and
do not display pro-death caspase activity. In addition, memory B
cells showed high degree of expression of several autophagy markers,
like LC3 and Atg7.
To undress the role of
authophagy in memory B cells, the authors created mice with B cell
specific deletion of autophagy gene Atg7 (CD19-cre Atg7 fl/fl).
Indeed, deletion of Atg7 in B cells resulted in a loss of resistance
of memory B cells to spontaneous cell death in an in vitro
culture. However, this increase of death in CD19-cre Atg7 fl/fl
memory B cell was
not caspase-dependent but was due to increase in sensitivity to the
oxidative stress, since it was significantly reversed by the use of
anti-oxidative agents like N-acethyl-L-cysteine (NAC) or
α-tocopherol.
Interestingly, CD19-cre
Atg7 fl/fl mice
displayed normal primary
antibody response to NP-KLH immunization (day 14), however, secondary
memory response (~ day 60 + day 5) was dramatically diminished
compared to control, wild-type mice. There was diminished secondary
response from bone marrow samples as well.
Kinetic
analysis indicated that memory B cell formation was normal until day
14 and then declined in CD19-cre Atg7 fl/fl
mice.
Significantly,
use of NAC or α-tocopherol
in vivo could rescue memory B cell decline and secondary antibody
response after immunization.
Finally,
the authors showed that CD19-cre Atg7 fl/fl
mice were highly sensitive to influenza infection even after prior
immunization.
In
summary, the authors proposed that deletion of Atg7 in B cells leads
to severe loss of memory B cells and failure to protect against
re-infection. Mechanistically, Atg7 deficiency impairs mitochondrial
function and leads to premature death of memory B cells due to excess
of ROS generation and lipid peroxidation.
One
difficulty interpreting these data has to do with the fact that both
memory B cell and long-lived plasma cells (LLPC) contribute to
secondary antibody response. Earlier study by Pengo N et al. (2),
clearly showed that autophagy deficiency impairs LLPC formation. It
is very difficult to differentiate between memory B cells role in
secondary response from that of LLPC. In Figures 4 and 5, there is
significant staining for IgG1-negative but antigen-specific
population in CD19-cre Atg7 fl/fl
mice. Are those cells LLPCs? Is autophagy required for memory B cell
survival or their secondary differentiation into plasma cells? Why is
autophagy essential for survival of memory B cells which supposedly
are quiet population in absence of antigen?
David
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