Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria
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Evaluation Summary:
The unexpected key finding is that T-cell-independent B cell activation engages the intracellular protein kinase PKC-delta to induce the necessary machinery of altered gene transcription culminating in IgG production. The methodology and the experimental setting are well-controlled, although how exactly B-cell stimulation by T-cell-independent antigens triggers PKC-delta remains to be elucidated.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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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.
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Evaluation Summary:
The unexpected key finding is that T-cell-independent B cell activation engages the intracellular protein kinase PKC-delta to induce the necessary machinery of altered gene transcription culminating in IgG production. The methodology and the experimental setting are well-controlled, although how exactly B-cell stimulation by T-cell-independent antigens triggers PKC-delta remains to be elucidated.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
T cell-independent type 2 (TI-2) antigen represents highly repetitive multivalent molecule such as bacterial capsular polysaccharides and viral capsids. Although B cell receptor play role in the center of antibody response to TI-2 antigen, necessary signaling molecules for isotype switched antibody production are unknown. In the present work, Fukao et al. first described that IL-1 and IFN-α promote TI-2-induced class switch recombination (CSR) to IgG3 primarily. They identified that Protein Kinase Cδ (PKCδ) and downstream transcriptional regulator, BATF, play critical role in IgG production stimulated by TI-2 antigen as well as commensal bacteria. Present study must be important work in the B cell biology field providing valuable data to understand immune response occurred against TI-2 antigens. Overall …
Reviewer #1 (Public Review):
T cell-independent type 2 (TI-2) antigen represents highly repetitive multivalent molecule such as bacterial capsular polysaccharides and viral capsids. Although B cell receptor play role in the center of antibody response to TI-2 antigen, necessary signaling molecules for isotype switched antibody production are unknown. In the present work, Fukao et al. first described that IL-1 and IFN-α promote TI-2-induced class switch recombination (CSR) to IgG3 primarily. They identified that Protein Kinase Cδ (PKCδ) and downstream transcriptional regulator, BATF, play critical role in IgG production stimulated by TI-2 antigen as well as commensal bacteria. Present study must be important work in the B cell biology field providing valuable data to understand immune response occurred against TI-2 antigens. Overall conclusions seems appropriately led. Considering that PKCδ is known as a key signaling molecule suppressing autoimmune diseases, results may suggest possible connection between TI-2 response and autoimmune diseases. Although following points could be a future issue, weakness of this study are, 1) Why and how PKCδ is required differently downstream of TI-2 BCR crosslinking but not in TD antigen exposure has not been addressed. 2) How IL-1α/β, IFNα or TLR ligands synergistically regulates Aicda gene expression together with BATF is still obscure.
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Reviewer #2 (Public Review):
The ligation of the B cell antigen receptor (BCR) by multivalent and repetitively arranged haptens can elicit the production of class-switched Ig isotypes such as IgG without the necessity of T cell help. How exactly these so-called T cell-independent type 2 (TI-2) antigens bypass the need of co-stimulatory signals through CD40 or other co-receptors in the course of T cell-dependent responses is unclear. One hypothesis states that based on their multivalency, TI-2 antigens cluster the BCR more potently compared to T cell-dependent antigens, and hence, the different signaling capabilities of the two types of B cell antigens might be quantitative rather than qualitative. The work by Fukao and colleagues challenges that view by providing compelling evidence for a more unique and specific role of protein kinase …
Reviewer #2 (Public Review):
The ligation of the B cell antigen receptor (BCR) by multivalent and repetitively arranged haptens can elicit the production of class-switched Ig isotypes such as IgG without the necessity of T cell help. How exactly these so-called T cell-independent type 2 (TI-2) antigens bypass the need of co-stimulatory signals through CD40 or other co-receptors in the course of T cell-dependent responses is unclear. One hypothesis states that based on their multivalency, TI-2 antigens cluster the BCR more potently compared to T cell-dependent antigens, and hence, the different signaling capabilities of the two types of B cell antigens might be quantitative rather than qualitative. The work by Fukao and colleagues challenges that view by providing compelling evidence for a more unique and specific role of protein kinase C-delta (PKC-delta) in TI-2 B cell responses. This conclusion is based on carefully controlled sets of in vitro and in vivo experiments showing that loss of PKC-delta expression in B cells basically abrogates class-switch recombination to and production of IgG3 antibodies associated with compromised protection against bacteremia. The key function of PKC-delta in TI-2 responses appears to be the induction of the transcription factor BATF that is critical for the expression of the Aicda gene, encoding the class-switching factor Activation-induced Cytidine Deaminase (AID).
Clear strengths of this work are the well-performed studies to monitor B cell functions at all levels by using appropriate mouse models e.g. measuring antibody production in response to hapten immunization or bacterial challenge, or monitoring BCR signaling events and gene expression profiles. The combination of these different read-out systems is sound and renders the data convincing. What is less clear or could be improved is the working model of how BCR ligation by TI-2 antigens translates into PKC-delta activation (Figure 7) while that by T cell-dependent antigens does not or is at least less efficient in terms of kinetic and extent of PKC-delta activation (Figure 2A and others). And what exactly then is the role of secondary stimulation? The presented data and the discussion are a bit weak on these aspects as well as on the obvious role of marginal zone B cells, which represent the main source of IgG3 and possess a particularly low activation threshold. To this reviewer, these aspects are not just additional details that would be helpful to assess. These points address the original and basic question raised above, namely, is it the quantity or the quality of BCR signal output (or BCR signal strength) that accounts for differences in biological B cell responses?
The concept provided in this manuscript on the role of PKC-delta as a decisive BCR signal effector that "distinguishes" TI-2 from T cell-dependent B cell responses is intriguing and will stimulate further discussions on this important aspect of humoral immunity.
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