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Defective metabolic reprogramming caused by SLC5A6 mutations disrupts germinal center B cell differentiation and vaccination-induced antibody responses 3450

Year: 2025
Type: article
Abstract: Description Adaptive immune cell maturation relies on efficient metabolic reprogramming to support antigen-driven responses. We investigated a family with novel compound heterozygous mutations in SLC5A6, encoding a multivitamin transporter linked to biotin deficiency presenting with antibody deficiency despite normal T and B cell counts. A CRISPR-Cas9 gene-edited mouse model with one of the corresponding mutations (Slc5a6M60K) was characterized for the immune defects caused by the mutant gene. Single-cell RNA sequencing of mouse B cells identified 21 distinct B cell clusters, which showed significant changes in distribution in the mutant mice. Plasma cell formation genes (Irf4, Jchain, Sdc1, Xbp1, Prdm1) were downregulated in plasmablasts, while memory B cell differentiation genes (Hhex, Tle3) remained stable. Analyses on follicular B cells revealed reduced germinal center markers (Aicda, Mki67) and DZ expansion genes (Cxcr4, Foxo1, Ccnd3) in the Slc5a6M60K mice, which recovered with biotin while LZ activation genes (Cd83, Myc, Syk, Akt) were unaffected. RNA velocity analyses confirmed impaired differentiation into plasma cells, DZ B cells, and atypical B cells in Slc5a6M60K mice after vaccination. Clonality analysis showed expanded clones only in WT and biotin-treated mutants. Biotin treatment restored SARS-CoV-2 spike-specific antibody responses to a COVID-19 vaccine in the Slc5a6M60K mice. Funding Sources Supported by NSTC 113-2314-B-006-102-MY3; National Applied Research Laboratories National Laboratory Animal Center (Taiwan) Topic Categories Immune Mechanisms of Human Disease (HUM)
DOI: 10.1093/jimmun/vkaf283.1255
Authors: Chu-Han Hsieh, Ying-Chen Tsai, Chi-Chang K. Shieh
Language: English
Subfield: Immunology
Open Access status: bronze
OpenAlex ID: W4416448189
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