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Written by | Tang Xiao Sugar
immune memory can respond faster and stronger when exposed to the same or similar pathogens again, and its humoral part is composed of memory B cells (MBCs) and longevity plasma cells (Long-lived plasma cells, PCs), dependent on germinal centers [1].
MBCs can still be detected decades after human infection or vaccination, and the mechanism of their longevity remains unclear [2-3].
Smallpox was officially eradicated in 1980 and smallpox virus-based vaccination was phased out, so any detectable virus-specific memory B cells after 2010 may have been produced
more than 40 years ago.
Previous studies have found that after a contraction phase in the first few years after immunization, a very stable plateau is reached and can last for decades, accounting for about 0.
1% of the total circulating IgG+ MBC [2-3].
However, the functional analysis of this long-lived MBC remains unknown
.
Recently, the team of Jean-Claude Weill and Claude-Agnes Reynaud of the University of Cité in Paris published an online report on Immunity Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting research paper, The team has previously reported that the spleen is enriched with these long-lived pox seedling-specific MBCs, and this study describes the isolation and functional study
of anti-acne seedlings MBCs in human spleen more than 40 years after vaccination.
The researchers first found that pox seedling glycoprotein B5-specific B cells were present in spleen IgG+ cells rather than IgM+CD27+ or IgA+, and that MBCs were detected in 85 percent of donors born before 1970 but not after birth in 1977, and these MBCs were very stable
for three decades 。 Sorting culture validation showed that B5-specific IgG+ MBCs were enriched in the CD73+CD21+ subpopulation, which was consistent
with single-cell sequencing results.
Further VH sequencing, clonal clustering, and MBC monoclonal antibody functional analysis showed that B5-specific IgG+ MBCs showed significant clonal expansion and somatic high-frequency mutations, with the first five clones accounting for 61%-84%
of all sequences in donor analysis.
Based on the distribution of VH mutations and affinities within clones, it can be seen that diversity is further limited within clones, and all clones show strong convergence
at the level of affinity and CDR3 sequence.
These results suggest the role
of broad clonal selection and BCR affinity in the initial selection and survival of long-lived MBCs.
In order to better understand CD21hi and CD21int, the two main B5-specific IgG+ spleen MBC subsets, the researchers analyzed the single-cell sequencing results and compared transcription characteristics and gene enrichment analysis, and found that these two groups of cells were far away from the initial B cells, and compared with the CD21int transition cell population, the CD21hi cell population had 346 unique genetic characteristics.
Multiple metabolism-related pathways include protein synthesis, glycolysis, oxidative phosphorylation, and upstream MYC activation, as well as the gradual upregulation
of NOTCH signaling from naïve B cells to CD21int cells to CD21hi cells.
Three transcription factors, MYC, ETV6 and HES1, were expressed at the highest levels in the CD21hi cell population, and RNA-seq and ATAC-seq also highlighted the enrichment expression
of NOTCH, MYC and metabolic pathways.
In addition, key genes such as key surface receptors and inhibitors, survival, cell interaction or migration related to BCR signaling were also enriched in the CD21hi cell population, while KLF2 and its inducing genes were downregulated
in the CD21hi cell population.
Flow cytometry results verified that integrins and adhesion molecules associated with spleen marginal region retention were expressed increased in CD21hi IgG+ MBCs, such as LFA-1 and ICAM1 reaching the level of
marginal zone B cells.
Compared with CD21int IgG+ MBCs, NOTCH-regulated surface molecules and markers of some marginal B cells are upregulated
.
Thus, CD21hi IgG+ spleen MBCs share some phenotype and homing potential with marginal zone B cells, and transcriptome data also indicate enhanced metabolic activity of MBCs
.
Telomere length is the key to cell longevity, and the researchers found that there was a significant difference in telomere point intensity between IgG+CD27+MBCs and untype-transformed IgD+CD27+ marginal zone B cells, and the fluorescence intensity of IgG+ MBCs increased significantly, indicating that telomere length was elongated, which was further confirmed
by the classical telomere restriction fragment detection 。 Further analysis combined with donor information showed that telomere length gradually decreased with age, and B5+CD27+IgG+MBC decreased telomere length compared with other CD27+IgG+MBC, indicating that the former was produced
more than 50 years ago.
These data suggest that telomeres are selectively elongated in GC-dependent MBCs and persist for decades, allowing long-term protection
against aging in these long-lived somatic cells.
Overall, the researchers isolated and analyzed B5-specific MBCs from people vaccinated more than 40 years ago, and only a few clones that exhibited limited intraclone diversity, which were enriched in CD21hiCD20hi IgG+, persisted for a long time In the subpopulation of spleen B cells, NOTCH/MYC expression characteristics in the marginal region are exhibited
.
In addition, the telomeres of B5-specific long-lived MBCs are longer than
those of other B cells and naïve B cells.
These results establish a mechanism that collectively modulates the functional longevity of MBC, including early telomere lengthening, affinity
selection during systole, and dependence on specific environments.
Original address: https://doi.
org/10.
1016/j.
immuni.
2022.
08.
019
Platemaker: Eleven
1.
Victora, G.
D.
, and Nussenzweig, M.
C.
(2012).
Germinal centers.
Annu.
Rev.
Immunol.
30, 429–457.
https://doi.
org/10.
1146/annurev-immunol- 020711-075032.
2.
Crotty, S.
, Felgner, P.
, Davies, H.
, Glidewell, J.
, Villarreal, L.
, and Ahmed, R.
(2003).
Cutting edge: long-term B cell memory in humans after smallpox vacci- nation.
J.
Immunol.
171, 4969–4973.
https://doi.
org/10.
4049/jimmunol.
171.
10.
4969.
3.
Amanna, I.
J.
, Carlson, N.
E.
, and Slifka, M.
K.
(2007).
Duration of humoral immu- nity to common viral and vaccine antigens.
N.
Engl.
J.
Med.
357, 1903–1915.
immune memory can respond faster and stronger when exposed to the same or similar pathogens again, and its humoral part is composed of memory B cells (MBCs) and longevity plasma cells (Long-lived plasma cells, PCs), dependent on germinal centers [1].
MBCs can still be detected decades after human infection or vaccination, and the mechanism of their longevity remains unclear [2-3].
Smallpox was officially eradicated in 1980 and smallpox virus-based vaccination was phased out, so any detectable virus-specific memory B cells after 2010 may have been produced
more than 40 years ago.
Previous studies have found that after a contraction phase in the first few years after immunization, a very stable plateau is reached and can last for decades, accounting for about 0.
1% of the total circulating IgG+ MBC [2-3].
However, the functional analysis of this long-lived MBC remains unknown
.
Recently, the team of Jean-Claude Weill and Claude-Agnes Reynaud of the University of Cité in Paris published an online report on Immunity Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting research paper, The team has previously reported that the spleen is enriched with these long-lived pox seedling-specific MBCs, and this study describes the isolation and functional study
of anti-acne seedlings MBCs in human spleen more than 40 years after vaccination.
The researchers first found that pox seedling glycoprotein B5-specific B cells were present in spleen IgG+ cells rather than IgM+CD27+ or IgA+, and that MBCs were detected in 85 percent of donors born before 1970 but not after birth in 1977, and these MBCs were very stable
for three decades 。 Sorting culture validation showed that B5-specific IgG+ MBCs were enriched in the CD73+CD21+ subpopulation, which was consistent
with single-cell sequencing results.
Further VH sequencing, clonal clustering, and MBC monoclonal antibody functional analysis showed that B5-specific IgG+ MBCs showed significant clonal expansion and somatic high-frequency mutations, with the first five clones accounting for 61%-84%
of all sequences in donor analysis.
Based on the distribution of VH mutations and affinities within clones, it can be seen that diversity is further limited within clones, and all clones show strong convergence
at the level of affinity and CDR3 sequence.
These results suggest the role
of broad clonal selection and BCR affinity in the initial selection and survival of long-lived MBCs.
In order to better understand CD21hi and CD21int, the two main B5-specific IgG+ spleen MBC subsets, the researchers analyzed the single-cell sequencing results and compared transcription characteristics and gene enrichment analysis, and found that these two groups of cells were far away from the initial B cells, and compared with the CD21int transition cell population, the CD21hi cell population had 346 unique genetic characteristics.
Multiple metabolism-related pathways include protein synthesis, glycolysis, oxidative phosphorylation, and upstream MYC activation, as well as the gradual upregulation
of NOTCH signaling from naïve B cells to CD21int cells to CD21hi cells.
Three transcription factors, MYC, ETV6 and HES1, were expressed at the highest levels in the CD21hi cell population, and RNA-seq and ATAC-seq also highlighted the enrichment expression
of NOTCH, MYC and metabolic pathways.
In addition, key genes such as key surface receptors and inhibitors, survival, cell interaction or migration related to BCR signaling were also enriched in the CD21hi cell population, while KLF2 and its inducing genes were downregulated
in the CD21hi cell population.
Flow cytometry results verified that integrins and adhesion molecules associated with spleen marginal region retention were expressed increased in CD21hi IgG+ MBCs, such as LFA-1 and ICAM1 reaching the level of
marginal zone B cells.
Compared with CD21int IgG+ MBCs, NOTCH-regulated surface molecules and markers of some marginal B cells are upregulated
.
Thus, CD21hi IgG+ spleen MBCs share some phenotype and homing potential with marginal zone B cells, and transcriptome data also indicate enhanced metabolic activity of MBCs
.
Telomere length is the key to cell longevity, and the researchers found that there was a significant difference in telomere point intensity between IgG+CD27+MBCs and untype-transformed IgD+CD27+ marginal zone B cells, and the fluorescence intensity of IgG+ MBCs increased significantly, indicating that telomere length was elongated, which was further confirmed
by the classical telomere restriction fragment detection 。 Further analysis combined with donor information showed that telomere length gradually decreased with age, and B5+CD27+IgG+MBC decreased telomere length compared with other CD27+IgG+MBC, indicating that the former was produced
more than 50 years ago.
These data suggest that telomeres are selectively elongated in GC-dependent MBCs and persist for decades, allowing long-term protection
against aging in these long-lived somatic cells.
Overall, the researchers isolated and analyzed B5-specific MBCs from people vaccinated more than 40 years ago, and only a few clones that exhibited limited intraclone diversity, which were enriched in CD21hiCD20hi IgG+, persisted for a long time In the subpopulation of spleen B cells, NOTCH/MYC expression characteristics in the marginal region are exhibited
.
In addition, the telomeres of B5-specific long-lived MBCs are longer than
those of other B cells and naïve B cells.
These results establish a mechanism that collectively modulates the functional longevity of MBC, including early telomere lengthening, affinity
selection during systole, and dependence on specific environments.
Original address: https://doi.
org/10.
1016/j.
immuni.
2022.
08.
019
Platemaker: Eleven
References
1.
Victora, G.
D.
, and Nussenzweig, M.
C.
(2012).
Germinal centers.
Annu.
Rev.
Immunol.
30, 429–457.
https://doi.
org/10.
1146/annurev-immunol- 020711-075032.
2.
Crotty, S.
, Felgner, P.
, Davies, H.
, Glidewell, J.
, Villarreal, L.
, and Ahmed, R.
(2003).
Cutting edge: long-term B cell memory in humans after smallpox vacci- nation.
J.
Immunol.
171, 4969–4973.
https://doi.
org/10.
4049/jimmunol.
171.
10.
4969.
3.
Amanna, I.
J.
, Carlson, N.
E.
, and Slifka, M.
K.
(2007).
Duration of humoral immu- nity to common viral and vaccine antigens.
N.
Engl.
J.
Med.
357, 1903–1915.
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