(3) Even within a GC-derived response, if you genetically label PCs prior to GC formation, you still get Long-lived plasma cells during this nascent extrafollicular response
Koike et al. here elegantly making use of two "timestamping" genetic tools
(4) Hai Qi and co. saw a similar IgM long-lived PC germline (no somatic hypermutations) repertoire enriched in public clones supporting the studies above
(6) One could have presumed this answer in the light of evolution since lampreys do not have germinal centers (personal communication) and indeed retain the features of long-lived antibody immunity (and live for ≤ 8 years)
(7) The second pervasive (rather intuitive) notion is that memory B cells replenish the long-lived PC pool based on a high-profile study using in vitro human memory B cells
(8) However, several studies in mice and macaques definitely dispelled this suggestion
via anti-CD20 depleting memory B cells and even removing lymph nodes and spleen.
(9) The third dogma is that plasma cells once they find their "effector" sites (i.e. bone marrow or intestines...etc) become immotile and just sit around
(10) Fooksman and colleagues show in a paradigm-shifting study that BM PCs recirculate to other bones and the spleen even in the absence of immunization
(15) This finding may help explain why mice and humans have so few IgE plasma cells
It may be that they are continuously eliminated by what could help your conventional B cell survive.
(16) So the point is, some PCs still express surface BCRs that can competently signal...What does it mean?
Not sure yet.
(17) There remains 3 more intriguing phenomena that go against prevailing dogma, but I guess we should wait for these to be published by the various groups interested in plasma cells before musing on this platform.
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(2) Inflation: induction of memory [CD8+] T cells that increase in frequency over time to >10% of the entire T cell pool in blood and higher abundance in peripheral tissues (e.g. liver and lung)
(3) First reported (to my knowledge) in a mouse model of CMV (MCMV)
2/Kagan and co. address the outstanding question: How can you activate and program a dendritic cell to promote protective (including antitumor) immunity?
Same as, why have DC-based vaccines and all cancer vaccines failed thus far?
3/The key is in keeping the DC alive and active during stimulation.
Most adjuvants (e.g. LPS, alum, polyI:C) induce pyroptosis which (while triggering local inflammation) limits the activity and costimulatory potential of a dendritic cell
Most studies and perspectives focus on one mechanism of tolerance and few have seriously considered all these together in the context of T cell differentiation.
We attempted to draw a conceptual framework for the known tolerance checkpoints at each stage of the T cell lifespan
In summary, we present 6 main tolerance hallmarks:
Quiescence
Ignorance
Anergy
Exhaustion
Senescence
Death