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?