B cell receptor-induced IL-10 production from neonatal mouse CD19+CD43- cells depends on STAT5-mediated IL-6 secretion
Curation statements for this article:-
Curated by eLife
eLife assessment
The authors present valuable findings about the mechanisms inducing IL-10 production by B cells in neonates. The evidence supporting the claims of the authors is solid, although the manuscript would be strengthened by amendments to the presentation of the data and explanation of some experimental choices.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Newborns are unable to reach the adult-level humoral immune response partly due to the potent immunoregulatory role of IL-10. Increased IL-10 production by neonatal B cells has been attributed to the larger population of IL-10-producting CD43 + B-1 cells in neonates. Here, we show that neonatal mouse CD43 - non-B-1 cells also produce substantial amounts of IL-10 following B cell antigen receptor (BCR) activation. In neonatal mouse CD43 - non-B-1 cells, BCR engagement activated STAT5 under the control of phosphorylated forms of signaling molecules Syk, Btk, PKC, FAK, and Rac1. Neonatal STAT5 activation led to IL-6 production, which in turn was responsible for IL-10 production in an autocrine/paracrine fashion through the activation of STAT3. In addition to the increased IL-6 production in response to BCR stimulation, elevated expression of IL-6Rα expression in neonatal B cells rendered them highly susceptible to IL-6-mediated STAT3 phosphorylation and IL-10 production. Finally, IL-10 secreted from neonatal mouse CD43 - non-B-1 cells was sufficient to inhibit TNF-α secretion by macrophages. Our results unveil a distinct mechanism of IL-6-dependent IL-10 production in BCR-stimulated neonatal CD19 + CD43 - B cells.
Article activity feed
-
-
Author Response
Reviewer #1 (Public Review):
In this study, they demonstrate that neonatal mice produce more CD43- B cellderived IL-10 following anti-BCR stimulation than adult mice. This is due to autocrine mechanisms whereby anti-BCR stimulation leads to pSTAT5 upregulation and production of IL-6 which then enhances IL-10 production via pSTAT3. These are interesting results for the regulatory B cell field, demonstrating that signaling is different in adult vs neonatal B cells and in particular for researchers studying the mechanisms underpinning the enhanced susceptibility to infection. The authors in the main achieved their aim and the results support their conclusions. However, considering that other studies have previously addressed the mechanisms contributing to enhanced IL-10 production in neonates, in the manuscript, there …
Author Response
Reviewer #1 (Public Review):
In this study, they demonstrate that neonatal mice produce more CD43- B cellderived IL-10 following anti-BCR stimulation than adult mice. This is due to autocrine mechanisms whereby anti-BCR stimulation leads to pSTAT5 upregulation and production of IL-6 which then enhances IL-10 production via pSTAT3. These are interesting results for the regulatory B cell field, demonstrating that signaling is different in adult vs neonatal B cells and in particular for researchers studying the mechanisms underpinning the enhanced susceptibility to infection. The authors in the main achieved their aim and the results support their conclusions. However, considering that other studies have previously addressed the mechanisms contributing to enhanced IL-10 production in neonates, in the manuscript, there are some experimental decisions and data presentation decisions that at times need more explanation. An important additional comment is that the introduction/discussion is at times insufficiently referenced to put the data in context for non-experts in this field and that numbers in general are low for an in vitro study.
We have now updated the introduction and discussion to provide more insight into our study. We hope that our study is now more understandable for non-experts.
Reviewer #2 (Public Review):
This paper reports that neonatal CD43- B cells produce IL-10 upon BCR stimulation, which inhibits TNF-alpha secretion from the peritoneal macrophage. In the neonatal CD43- B cells, the BCR-mediated signal transmitted Stat5 activation and induced IL-6 production, and subsequently, the secreted IL-6 activated Stat3 finally leading to IL-10 production. The authors identified a unique signaling pathway leading to IL-10 production and revealed the different responses between CD43+ and CD43- B cells against BCR crosslinking. A weakness of this study is that the neonatal CD43- B cell subset secreting IL-10 has not been characterized and discussed as well. BCR expression levels between adult CD43- B cells and neonatal CD43- B cells have been overlooked to explain the different reactivity. Clarity on these points would substantially enhance the impact of the manuscript.
We thank the reviewer for the suggestion to measure BCR levels. We now measured the IgM and IgD levels on neonatal and adult B cell C43+ and CD43- subsets (Figure 1figure supplement 5).
-
eLife assessment
The authors present valuable findings about the mechanisms inducing IL-10 production by B cells in neonates. The evidence supporting the claims of the authors is solid, although the manuscript would be strengthened by amendments to the presentation of the data and explanation of some experimental choices.
-
Reviewer #1 (Public Review):
In this study, they demonstrate that neonatal mice produce more CD43- B cell-derived IL-10 following anti-BCR stimulation than adult mice. This is due to autocrine mechanisms whereby anti-BCR stimulation leads to pSTAT5 upregulation and production of IL-6 which then enhances IL-10 production via pSTAT3. These are interesting results for the regulatory B cell field, demonstrating that signaling is different in adult vs neonatal B cells and in particular for researchers studying the mechanisms underpinning the enhanced susceptibility to infection. The authors in the main achieved their aim and the results support their conclusions. However, considering that other studies have previously addressed the mechanisms contributing to enhanced IL-10 production in neonates, in the manuscript, there are some …
Reviewer #1 (Public Review):
In this study, they demonstrate that neonatal mice produce more CD43- B cell-derived IL-10 following anti-BCR stimulation than adult mice. This is due to autocrine mechanisms whereby anti-BCR stimulation leads to pSTAT5 upregulation and production of IL-6 which then enhances IL-10 production via pSTAT3. These are interesting results for the regulatory B cell field, demonstrating that signaling is different in adult vs neonatal B cells and in particular for researchers studying the mechanisms underpinning the enhanced susceptibility to infection. The authors in the main achieved their aim and the results support their conclusions. However, considering that other studies have previously addressed the mechanisms contributing to enhanced IL-10 production in neonates, in the manuscript, there are some experimental decisions and data presentation decisions that at times need more explanation. An important additional comment is that the introduction/discussion is at times insufficiently referenced to put the data in context for non-experts in this field and that numbers in general are low for an in vitro study.
-
Reviewer #2 (Public Review):
This paper reports that neonatal CD43- B cells produce IL-10 upon BCR stimulation, which inhibits TNF-alpha secretion from the peritoneal macrophage. In the neonatal CD43- B cells, the BCR-mediated signal transmitted Stat5 activation and induced IL-6 production, and subsequently, the secreted IL-6 activated Stat3 finally leading to IL-10 production. The authors identified a unique signaling pathway leading to IL-10 production and revealed the different responses between CD43+ and CD43- B cells against BCR crosslinking. A weakness of this study is that the neonatal CD43- B cell subset secreting IL-10 has not been characterized and discussed as well. BCR expression levels between adult CD43- B cells and neonatal CD43- B cells have been overlooked to explain the different reactivity. Clarity on these points …
Reviewer #2 (Public Review):
This paper reports that neonatal CD43- B cells produce IL-10 upon BCR stimulation, which inhibits TNF-alpha secretion from the peritoneal macrophage. In the neonatal CD43- B cells, the BCR-mediated signal transmitted Stat5 activation and induced IL-6 production, and subsequently, the secreted IL-6 activated Stat3 finally leading to IL-10 production. The authors identified a unique signaling pathway leading to IL-10 production and revealed the different responses between CD43+ and CD43- B cells against BCR crosslinking. A weakness of this study is that the neonatal CD43- B cell subset secreting IL-10 has not been characterized and discussed as well. BCR expression levels between adult CD43- B cells and neonatal CD43- B cells have been overlooked to explain the different reactivity. Clarity on these points would substantially enhance the impact of the manuscript.
-
