B cell hyperactivation in an Ackr4‐deficient mouse strain is not caused by lack of ACKR4 expression. Issue 6 (16th December 2019)

• Record Type: Journal Article
• Authors: Eckert, Nadine; Werth, Kathrin; Willenzon, Stefanie; Tan, Likai; Förster, Reinhold
• Is Part Of: Journal of leukocyte biology. Volume 107:Issue 6(2020)
• Page Start: 1155
• Page End: 1166
• Publication Date: 2019-12-16
• Subjects: congenic mice -- exome sequencing -- humoral immune response -- passenger mutation; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.2MA1119-300R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: The majority of genetically modified C57BL/6 mice contain congenic passenger DNA around the targeted gene locus as they were generated from 129‐derived embryonic stem cells (ESCs) with subsequent backcrossing to the C57BL/6 genetic background. When studying the role of atypical chemokine receptor 4 (ACKR4) in the immune system, we realized that the two available Ackr4 ‐deficient mouse strains ( Ackr4 −/− and Ackr4 GFP/GFP ) show profoundly different phenotypes: Compared to wild‐type and Ackr4 GFP/GFP mice, Ackr4 −/− mice show a strong accumulation of plasma blasts in mesenteric lymph node and spleen as well as increased B cell proliferation after in vitro activation. This phenotype was maintained after further backcrossing to C57BL/6 mice and was even present in heterozygous Ackr4 +/− animals, suggesting that a gene variant on the targeted chromosome might cause this phenotype. Exome sequencing revealed that a region of approximately 20 Mbp around the Ackr4 locus on chromosome 9 still originates from the 129 background based on high variant density observed. In activated Ackr4 −/− and Ackr4 GFP/GFP B cells, transcripts of genes around the Ackr4 locus were equally deregulated compared to C57BL/6 B cells, whereas increased expression of IL‐6 was selectively observed in B cells of Ackr4 −/− mice. Because the gene encoding for IL‐6 is placed on chromosome 5 these findings suggest that passenger DNA around the Ackr4 locus has an indirect effect on B cell activation and IL‐6 production. Results of the present study should not only lead to the reinterpretation of data from earlier studies using Ackr4 −/− mice but should remind the scientific community about the limitations of mouse models using mice created by gene‐targeting of nonsyngeneic ESCs. Abstract : Two independently generated Ackr4 ‐deficient mice have different phenotypes with regard to B cell activation and proliferation.