DGKα and ζ Deficiency Causes Regulatory T-Cell Dysregulation, Destabilization, and Conversion to Pathogenic T-Follicular Helper Cells to Trigger IgG1-Predominant Autoimmunity
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eLife Assessment
This study presents a valuable finding on the signaling mechanisms underlying Treg cell homeostasis by identifying the simultaneous requirement of diacylglycerol (DAG) kinases (DGK) alpha and zeta for Foxp3+ Treg cell function and follicular responses, with implications for the pathogenesis of some autoimmune diseases. Whereas data based on the characterization of double knock-out mice (for DGK alpha and zeta) is solid, showing the emergence of autoimmune manifestations, the study has gaps in its experimental approaches since it is not clear what can be attributed to the simultaneous DKGα and ζ deficiency, versus the individual deficiency of either one. Experiments on the pathogenic potential of the DKO Tregs in the absence of other T-cells were not presented and results on the role of CD25 downregulation and CD28-independent activation of Treg cells were not properly discussed. Nonetheless, the reported data would be of interest to immunologists working on T-cell intracellular signaling and autoimmunity.
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Abstract
Regulatory T cells (Tregs) actively engage in immune suppression to prevent autoimmune diseases but also inhibit anti-tumor immunity. Although Tregs express a TCR repertoire with relatively high affinities to self, they are normally quite stable and their inflammatory programs are intrinsically suppressed. We report here that diacylglycerol (DAG) kinases (DGK) ( and ( are crucial for homeostasis, suppression of proinflammatory programs, and stability of Tregs and for enforcing their dependence on CD28 costimulatory signal. Treg-specific deficiency of both DGK( and ( derails signaling, metabolic, and transcriptional programs in Tregs to cause dysregulated phenotypic and functional properties and to unleash conversion to pathogenic exTregs, especially exTreg-T follicular helper (Tfh) 2 cells, leading to uncontrolled effector T cell differentiation, deregulated germinal center (GC) B-cell responses and IgG1/IgE predominant antibodies/autoantibodies, and multiorgan autoimmune diseases. Our data not only illustrate the crucial roles of DGKs in Tregs to maintain self-tolerance but also unveil a Treg-to-self-reactive-pathogenic-exTreg-Tfh-cell program that is suppressed by DGKs and that could exert broad pathogenic roles in autoimmune diseases if unchecked.
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eLife Assessment
This study presents a valuable finding on the signaling mechanisms underlying Treg cell homeostasis by identifying the simultaneous requirement of diacylglycerol (DAG) kinases (DGK) alpha and zeta for Foxp3+ Treg cell function and follicular responses, with implications for the pathogenesis of some autoimmune diseases. Whereas data based on the characterization of double knock-out mice (for DGK alpha and zeta) is solid, showing the emergence of autoimmune manifestations, the study has gaps in its experimental approaches since it is not clear what can be attributed to the simultaneous DKGα and ζ deficiency, versus the individual deficiency of either one. Experiments on the pathogenic potential of the DKO Tregs in the absence of other T-cells were not presented and results on the role of CD25 downregulation and …
eLife Assessment
This study presents a valuable finding on the signaling mechanisms underlying Treg cell homeostasis by identifying the simultaneous requirement of diacylglycerol (DAG) kinases (DGK) alpha and zeta for Foxp3+ Treg cell function and follicular responses, with implications for the pathogenesis of some autoimmune diseases. Whereas data based on the characterization of double knock-out mice (for DGK alpha and zeta) is solid, showing the emergence of autoimmune manifestations, the study has gaps in its experimental approaches since it is not clear what can be attributed to the simultaneous DKGα and ζ deficiency, versus the individual deficiency of either one. Experiments on the pathogenic potential of the DKO Tregs in the absence of other T-cells were not presented and results on the role of CD25 downregulation and CD28-independent activation of Treg cells were not properly discussed. Nonetheless, the reported data would be of interest to immunologists working on T-cell intracellular signaling and autoimmunity.
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Reviewer #1 (Public review):
Summary:
The manuscript by Li and colleagues describes the impact of deficiency on the DKGα and ζ on Treg cells and follicular responses. The experimental approach is based on the characterization of double KO mice that show the emergence of autoimmune manifestations that include the production of autoantibodies. Additionally, there is an increase in Tfh cells, but also Tfr cells in these mice deficient in both DKGα and ζ. Although the observations are interesting, the interpretation of the observations is difficult in the absence of data related to single mutations. While a supplementary figure shows that the autoimmune manifestations are more severe in the DKGα and ζ deficient mice, prior observations show that a single DKGα deficiency has an impact on Treg homeostasis. As such, the contribution of the two …
Reviewer #1 (Public review):
Summary:
The manuscript by Li and colleagues describes the impact of deficiency on the DKGα and ζ on Treg cells and follicular responses. The experimental approach is based on the characterization of double KO mice that show the emergence of autoimmune manifestations that include the production of autoantibodies. Additionally, there is an increase in Tfh cells, but also Tfr cells in these mice deficient in both DKGα and ζ. Although the observations are interesting, the interpretation of the observations is difficult in the absence of data related to single mutations. While a supplementary figure shows that the autoimmune manifestations are more severe in the DKGα and ζ deficient mice, prior observations show that a single DKGα deficiency has an impact on Treg homeostasis. As such, the contribution of the two chains to the overall phenotype is hard to establish.
Strengths:
Well-conducted experiments with informative mouse models with defined genetic defects.
Weaknesses:
The major weakness is the lack of clarity concerning what can be attributed to simultaneous DKGα and ζ deficiency versus deficiency on DKGα or ζ alone.
Some interpretations are also not conclusively supported by data.
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Reviewer #2 (Public review):
Summary:
In this manuscript, Li et al investigate the combined role of diacylglycerol (DAG) kinases (DGK) a and z in Foxp3+ Treg cells function that prevent autoimmunity. The authors generated DGK a and z Treg-specific double knockout mice (DKO) by crossing Dgkalpha-/- mice to DgKzf and Foxp3YFPCre/+ mice. The resulting "DKO" mice thus lack DGK a in all cells and DGK z in Foxp3+Treg cells. The authors show that the DKO mice spontaneously develop autoimmunity, characterized by multiorgan inflammatory infiltration and elevated anti-double-strand DNA (dsDNA), -single-strand DNA (ssDNA), and -nuclear autoantibodies. The authors attribute the DKO mice phenotype to Foxp3+Treg dysfunction, including accelerated conversion into "exTreg" cells with pathogenic activity. Interestingly, the combined deficiency of DGK a …
Reviewer #2 (Public review):
Summary:
In this manuscript, Li et al investigate the combined role of diacylglycerol (DAG) kinases (DGK) a and z in Foxp3+ Treg cells function that prevent autoimmunity. The authors generated DGK a and z Treg-specific double knockout mice (DKO) by crossing Dgkalpha-/- mice to DgKzf and Foxp3YFPCre/+ mice. The resulting "DKO" mice thus lack DGK a in all cells and DGK z in Foxp3+Treg cells. The authors show that the DKO mice spontaneously develop autoimmunity, characterized by multiorgan inflammatory infiltration and elevated anti-double-strand DNA (dsDNA), -single-strand DNA (ssDNA), and -nuclear autoantibodies. The authors attribute the DKO mice phenotype to Foxp3+Treg dysfunction, including accelerated conversion into "exTreg" cells with pathogenic activity. Interestingly, the combined deficiency of DGK a and z seems to release Treg cell dependence on CD28-mediated costimulatory signals, which the authors show by crossing their DKO mice to CD28-/- mice (TKO mice), which also develop autoimmunity.
Strengths:
The phenotypes of the mutant mice described in the manuscript are striking, and the authors provide a comprehensive analysis of the functional processes altered by the lack of DGKs.
Weaknesses:
One aspect that could be better explored is the direct role of "ex-Tregs" in causing pathogenesis in the models utilized.
However, overall, this is an important report that makes a significant addition to the understanding of DAG kinases in Treg cell biology.
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