Loss of TET2 increases B-1 cell number and IgM production while limiting CDR3 diversity

• Published in: Frontiers in immunology Vol. 15; p. 1380641
• Main 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 27.03.2024
• Subjects: B cell receptor (BCR); B-1 cells; immunoglobulin M (IgM); Immunology; innate B cells; natural antibodies (Nab); ten-eleven translocation-2 (TET2); B cell receptor (BCR); immunoglobulin M (IgM); natural antibodies (Nab); complementarity-determining region-3 (CDR3); ten-eleven translocation-2 (TET2); innate B cells; B-1 cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1380641

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 V 11 and V 12 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.