Abstract
Antibody responses have been classified as being either T cell-dependent or T cell-independent (TI). TI antibody responses are further classified as being either type 1 (TI-1) or type 2 (TI-2), depending on their requirement for B cell-mediated antigen receptor signaling. Although the mechanistic basis of antibody responses has been studied extensively, it remains unclear whether different antibody responses share similarities in their transcriptional regulation. Here, we show that mice deficient in IκB-ζ, specifically in their B cells, have impaired TI-1 antibody responses but normal T cell-dependent and TI-2 antibody responses. The absence of IκB-ζ in B cells also impaired proliferation triggered by Toll-like receptor (TLR) activation, plasma cell differentiation, and class switch recombination (CSR). Mechanistically, IκB-ζ-deficient B cells could not induce TLR-mediated induction of activation-induced cytidine deaminase (AID), a class-switch DNA recombinase. Retroviral transduction of AID in IκB-ζ-deficient B cells restored CSR activity. Furthermore, acetylation of histone H3 in the vicinity of the transcription start site of the gene that encodes AID was reduced in IκB-ζ-deficient B cells relative to IκB-ζ-expressing B cells. These results indicate that IκB-ζ regulates TLR-mediated CSR by inducing AID. Moreover, IκB-ζ defines differences in the transcriptional regulation of different antibody responses.
Highlights
IB-, a member of the IB family of nuclear proteins that regulates transcription, can be induced by Toll-like receptor (TLR) signaling
Mice Deficient in IB- in Their B Cells Have Impaired T cell-independent (TI)-1 Antibody Responses—The transcriptional regulator IB- can be up-regulated by B cell antigen receptor (BCR)- or LPS-mediated stimulation of B cells through transcriptional and/or posttranscriptional regulation [24]
We have used in vivo and in vitro assays to show that TLR-mediated TI-1, but not T cell-dependent (TD) or TI-2, antibody responses are impaired in cKO mice
Summary
IB-, a member of the IB family of nuclear proteins that regulates transcription, can be induced by Toll-like receptor (TLR) signaling. The absence of IB- in B cells impaired proliferation triggered by Toll-like receptor (TLR) activation, plasma cell differentiation, and class switch recombination (CSR). Acetylation of histone H3 in the vicinity of the transcription start site of the gene that encodes AID was reduced in IB--deficient B cells relative to IB--expressing B cells These results indicate that IB- regulates TLR-mediated CSR by inducing AID. We showed that a deficiency in IB--impaired TLR induced proliferation, CSR, and differentiation of plasma cells. IB- is essential for the co-stimulation of either TLR2 or TLR9 with BCR to ensure CSR These findings indicate that the IB--regulated transcriptional network controls TLR-mediated antibody responses. These results reveal that IB- defines a key distinction between TD and TI antibody responses
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