Abstract
Antigens (Ags) with multivalent and repetitive structure elicit IgG production in a T-cell-independent manner. However, the mechanisms by which such T-cell-independent type-2 (TI-2) Ags induce IgG responses remain obscure. Here, we report that B-cell receptor (BCR) engagement with a TI-2 Ag but not with a T-cell-dependent (TD) Ag was able to induce the transcription of Aicda encoding activation-induced cytidine deaminase (AID) and efficient class switching to IgG3 upon costimulation with IL-1 or IFN-α in mouse B cells. TI-2 Ags strongly induced the phosphorylation of protein kinase C (PKC)δ and PKCδ mediated the Aicda transcription through the induction of BATF, the key transcriptional regulator of Aicda. In PKCδ-deficient mice, production of IgG was intact against TD Ag but abrogated against typical TI-2 Ags as well as commensal bacteria, and experimental disruption of the gut epithelial barrier resulted in fatal bacteremia. Thus, our results have revealed novel molecular requirements for class switching in the TI-2 response and highlighted its importance in homeostatic commensal-specific IgG production.
Highlights
Ag-specific antibody production is essential for humoral immunity
A TI-2 Ag induces B-cell proliferation and potentiates CSR to IgG Considering the unique structure of TI-2 Ags, it is plausible that the engagement of the B cell receptor (BCR) with TI-2 Ags and TD Ags differently induces downstream signaling that leads to B cell activation, this idea has not been tested properly so far
NP-Ficoll or each of these cytokines alone could not induce those responses (Figure 102 1 C-E). These results indicate that BCR signaling elicited by TI-2 Ag-engagement is pivotal for the TI-2 B-cell response, namely induction of proliferation and antibody production, as well as potentiation of CSR to IgG. 106 PKCδ is required for IgG production and AID expression induced by TI-2 Ag stimulation By Western blot analyses for BCR signaling using NP-specific B cells, we noticed that NP-Ficoll induced phosphorylation of PKCδ tyrosine 311 (Y311), indicative of activation of the kinase 109 (Balasubramanian et al, 2006), more strongly than NP-CGG (Figure 2 A)
Summary
Antigens (Ags) with multivalent and repetitive structure elicit IgG production in a T cell-independent manner. The mechanisms by which such T cell-independent type-2 (TI-2) Ags induce IgG responses remain obscure. TI-2 Ags strongly induced the phosphorylation of protein kinase C (PKC)δ and PKCδ mediated the Aicda transcription through the induction of BATF, the key transcriptional regulator of Aicda. In PKCδ-deficient mice, production of IgG was intact against TD Ag but abrogated against typical TI-2 Ags as well as commensal bacteria, and experimental disruption of the gut epithelial barrier resulted in fatal bacteremia. Our results have revealed novel molecular requirements for class-switching in the TI-2 response and highlighted its importance in homeostatic commensal-specific IgG production
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