Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1380641/full |
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| author | Emily Dennis Emily Dennis Maria Murach Maria Murach Cassidy M.R. Blackburn Melissa Marshall Katherine Root Tanyaporn Pattarabanjird Justine Deroissart Loren D. Erickson Loren D. Erickson Christoph J. Binder Stefan Bekiranov Stefan Bekiranov Coleen A. McNamara Coleen A. McNamara |
| author_facet | Emily Dennis Emily Dennis Maria Murach Maria Murach Cassidy M.R. Blackburn Melissa Marshall Katherine Root Tanyaporn Pattarabanjird Justine Deroissart Loren D. Erickson Loren D. Erickson Christoph J. Binder Stefan Bekiranov Stefan Bekiranov Coleen A. McNamara Coleen A. McNamara |
| author_sort | Emily Dennis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T18:46:50Z |
| format | Article |
| id | doaj.art-e381fe19acd54eb697d2fdd0ef3acea1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-24T18:46:50Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e381fe19acd54eb697d2fdd0ef3acea12024-03-27T05:02:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-03-011510.3389/fimmu.2024.13806411380641Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversityEmily Dennis0Emily Dennis1Maria Murach2Maria Murach3Cassidy M.R. Blackburn4Melissa Marshall5Katherine Root6Tanyaporn Pattarabanjird7Justine Deroissart8Loren D. Erickson9Loren D. Erickson10Christoph J. Binder11Stefan Bekiranov12Stefan Bekiranov13Coleen A. McNamara14Coleen A. McNamara15Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment for Laboratory Medicine, Medical University of Vienna, Vienna, AustriaBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, United StatesDepartment for Laboratory Medicine, Medical University of Vienna, Vienna, AustriaBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDepartment of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United StatesBeirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United StatesDivision of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United StatesRecent 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.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1380641/fullinnate B cellsB-1 cellsten-eleven translocation-2 (TET2)natural antibodies (Nab)immunoglobulin M (IgM)B cell receptor (BCR) |
| spellingShingle | Emily Dennis Emily Dennis Maria Murach Maria Murach Cassidy M.R. Blackburn Melissa Marshall Katherine Root Tanyaporn Pattarabanjird Justine Deroissart Loren D. Erickson Loren D. Erickson Christoph J. Binder Stefan Bekiranov Stefan Bekiranov Coleen A. McNamara Coleen A. McNamara Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity Frontiers in Immunology innate B cells B-1 cells ten-eleven translocation-2 (TET2) natural antibodies (Nab) immunoglobulin M (IgM) B cell receptor (BCR) |
| title | Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity |
| title_full | Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity |
| title_fullStr | Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity |
| title_full_unstemmed | Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity |
| title_short | Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity |
| title_sort | loss of tet2 increases b 1 cell number and igm production while limiting cdr3 diversity |
| topic | innate B cells B-1 cells ten-eleven translocation-2 (TET2) natural antibodies (Nab) immunoglobulin M (IgM) B cell receptor (BCR) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1380641/full |
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