| Title: |
Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity. |
| Authors: |
Dennis, Emily, Murach, Maria, Blackburn, Cassidy M. R., Marshall, Melissa, Root, Katherine, Pattarabanjird, Tanyaporn, Deroissart, Justine, Erickson, Loren D., Binder, Christoph J., Bekiranov, Stefan, McNamara, Coleen A. |
| Source: |
Frontiers in Immunology; 2024, p1-16, 16p |
| Subject Terms: |
PLASMA cells, IMMUNOGLOBULIN heavy chains, IMMUNOGLOBULIN light chains, IMMUNOGLOBULIN genes, GERMINAL centers |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
