TACI expression and plasma cell differentiation are impaired in the absence of functional IκBNS. Issue 5 (30th January 2019)

• Record Type: Journal Article
• Authors: Khoenkhoen, Sharesta; Erikson, Elina; Ádori, Monika; Stark, Julian M; Scholz, Jean L; Cancro, Michael P; Pedersen, Gabriel K; Karlsson Hedestam, Gunilla B
• Is Part Of: Immunology and cell biology. Volume 97:Issue 5(2019)
• Page Start: 485
• Page End: 497
• Publication Date: 2019-01-30
• Subjects: APRIL -- IκBNS -- nfkbid -- NF‐κB -- plasma cell differentiation -- TACI; Immunology -- Periodicals; Cytology -- Periodicals; 616.079
• DOI: 10.1111/imcb.12228
• Languages: English
• ISSNs: 0818-9641

Abstract

Abstract: Impaired classical NF‐κB pathway signaling causes reduced antibody responses to T‐independent (TI) antigens. We investigated the potential reasons for defective TI responses in mice lacking the atypical inhibitory kappa B (IκB) protein of the NF‐κB pathway, IκBNS. Analyses of the plasma cell compartment in vitro and in vivo after challenge with lipopolysaccharide (LPS) showed significant decreases in the frequencies of plasma cells in the absence of IκBNS. In vitro activation of B cells via the B cell receptor or via Toll‐like receptor 4 revealed that early activation events were unaffected in IκBNS‐deficient B cells, while proliferation was reduced compared to in similarly stimulated wildtype (wt) B cells. IκBNS‐deficient B cells also displayed impaired upregulation of the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), which is essential for TI responses, and decreased sensitivity to TACI ligands upon stimulation. Furthermore, IκBNS‐deficient B cells, in contrast to wt B cells, displayed altered expression of IRF4, Blimp‐1 and Pax5 upon LPS‐induced differentiation, indicating impaired transcriptional regulation of plasma cell generation. Abstract : This study identified alterations in B cell activation and plasma cell differentiation as underlying reasons for the impaired humoral responses against T‐independent (TI) antigens associated with IκBNS deficiency. In the absence of IκBNS, B cells exhibited reduced proliferative capacity, a loss of TACI‐mediated antibody production, and altered expression of the transcription factors Pax5, IRF4 and Blimp‐1, and fail to generate plasma cells. These findings indicate that TACI function and plasma cell differentiation are regulated by IκBNS, and may help explain mechanisms for impaired TI responses associated with defects in components of the NF‐κB signaling pathway.