Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity
Copyright © 2024 Dennis, Murach, Blackburn, Marshall, Root, Pattarabanjird, Deroissart, Erickson, Binder, Bekiranov and McNamara..
Recent studies have demonstrated a role for Ten-Eleven Translocation-2 (TET2), an epigenetic modulator, in regulating germinal center formation and plasma cell differentiation in B-2 cells, yet the role of TET2 in regulating B-1 cells is largely unknown. Here, B-1 cell subset numbers, IgM production, and gene expression were analyzed in mice with global knockout of TET2 compared to wildtype (WT) controls. Results revealed that TET2-KO mice had elevated numbers of B-1a and B-1b cells in their primary niche, the peritoneal cavity, as well as in the bone marrow (B-1a) and spleen (B-1b). Consistent with this finding, circulating IgM, but not IgG, was elevated in TET2-KO mice compared to WT. Analysis of bulk RNASeq of sort purified peritoneal B-1a and B-1b cells revealed reduced expression of heavy and light chain immunoglobulin genes, predominantly in B-1a cells from TET2-KO mice compared to WT controls. As expected, the expression of IgM transcripts was the most abundant isotype in B-1 cells. Yet, only in B-1a cells there was a significant increase in the proportion of IgM transcripts in TET2-KO mice compared to WT. Analysis of the CDR3 of the BCR revealed an increased abundance of replicated CDR3 sequences in B-1 cells from TET2-KO mice, which was more clearly pronounced in B-1a compared to B-1b cells. V-D-J usage and circos plot analysis of V-J combinations showed enhanced usage of VH11 and VH12 pairings. Taken together, our study is the first to demonstrate that global loss of TET2 increases B-1 cell number and IgM production and reduces CDR3 diversity, which could impact many biological processes and disease states that are regulated by IgM.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Frontiers in immunology - 15(2024) vom: 27., Seite 1380641 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Dennis, Emily [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 12.04.2024 Date Revised 25.04.2024 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.3389/fimmu.2024.1380641 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370904613 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370904613 | ||
| 003 | DE-627 | ||
| 005 | 20240425233820.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240411s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fimmu.2024.1380641 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1386.xml |
| 035 | |a (DE-627)NLM370904613 | ||
| 035 | |a (NLM)38601144 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Dennis, Emily |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.04.2024 | ||
| 500 | |a Date Revised 25.04.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 Dennis, Murach, Blackburn, Marshall, Root, Pattarabanjird, Deroissart, Erickson, Binder, Bekiranov and McNamara. | ||
| 520 | |a Recent studies have demonstrated a role for Ten-Eleven Translocation-2 (TET2), an epigenetic modulator, in regulating germinal center formation and plasma cell differentiation in B-2 cells, yet the role of TET2 in regulating B-1 cells is largely unknown. Here, B-1 cell subset numbers, IgM production, and gene expression were analyzed in mice with global knockout of TET2 compared to wildtype (WT) controls. Results revealed that TET2-KO mice had elevated numbers of B-1a and B-1b cells in their primary niche, the peritoneal cavity, as well as in the bone marrow (B-1a) and spleen (B-1b). Consistent with this finding, circulating IgM, but not IgG, was elevated in TET2-KO mice compared to WT. Analysis of bulk RNASeq of sort purified peritoneal B-1a and B-1b cells revealed reduced expression of heavy and light chain immunoglobulin genes, predominantly in B-1a cells from TET2-KO mice compared to WT controls. As expected, the expression of IgM transcripts was the most abundant isotype in B-1 cells. Yet, only in B-1a cells there was a significant increase in the proportion of IgM transcripts in TET2-KO mice compared to WT. Analysis of the CDR3 of the BCR revealed an increased abundance of replicated CDR3 sequences in B-1 cells from TET2-KO mice, which was more clearly pronounced in B-1a compared to B-1b cells. V-D-J usage and circos plot analysis of V-J combinations showed enhanced usage of VH11 and VH12 pairings. Taken together, our study is the first to demonstrate that global loss of TET2 increases B-1 cell number and IgM production and reduces CDR3 diversity, which could impact many biological processes and disease states that are regulated by IgM | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a B cell receptor (BCR) | |
| 650 | 4 | |a B-1 cells | |
| 650 | 4 | |a complementarity-determining region-3 (CDR3) | |
| 650 | 4 | |a immunoglobulin M (IgM) | |
| 650 | 4 | |a innate B cells | |
| 650 | 4 | |a natural antibodies (Nab) | |
| 650 | 4 | |a ten-eleven translocation-2 (TET2) | |
| 650 | 7 | |a Immunoglobulin Light Chains |2 NLM | |
| 650 | 7 | |a Immunoglobulin M |2 NLM | |
| 700 | 1 | |a Murach, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Blackburn, Cassidy M R |e verfasserin |4 aut | |
| 700 | 1 | |a Marshall, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a Root, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Pattarabanjird, Tanyaporn |e verfasserin |4 aut | |
| 700 | 1 | |a Deroissart, Justine |e verfasserin |4 aut | |
| 700 | 1 | |a Erickson, Loren D |e verfasserin |4 aut | |
| 700 | 1 | |a Binder, Christoph J |e verfasserin |4 aut | |
| 700 | 1 | |a Bekiranov, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a McNamara, Coleen A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in immunology |d 2010 |g 15(2024) vom: 27., Seite 1380641 |w (DE-627)NLM215811453 |x 1664-3224 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g day:27 |g pages:1380641 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3389/fimmu.2024.1380641 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |b 27 |h 1380641 | ||