Diacylglycerol Kinases Balance DAG Signaling to Control B Cell Maturation, Germinal Center Homeostasis, and Humoral Immunity
- 1Duke University School of Medicine
Abstract
Diacylglycerol (DAG) is a critical second messenger downstream of the B-cell receptor (BCR), but how DAG signaling is regulated during B-cell development and humoral responses remains incompletely understood. Here, complementary gain- and loss-of-function approaches revealed stage-specific requirements for diacylglycerol kinase (DGK)-regulated signaling in B cells. Expression of the gain-of-function DGK{zeta} mutant DGK{zeta}{Delta}NLS had limited effects on early BM B-cell development but progressively impaired transitional and mature B-cell populations. DGK{zeta}{Delta}NLS attenuated BCR-induced ERK1/2 and mTOR signaling, activation, and proliferation and, when expressed in AID-expressing B cells, reduced GC B-cell survival and T-dependent IgG responses without detectably impairing GC B-cell proliferation in vivo. Conversely, combined DGK/{zeta} deficiency resulted in marked spontaneous GC B-cell expansion associated with enhanced ERK1/2, Akt, and S6 signaling and increased glucose uptake. Despite this steady-state GC expansion, DGK/{zeta}-deficient mice developed spontaneous autoreactivity and mounted impaired antigen-specific antibody responses. Thus, B-cell developmental stages exhibit differential sensitivity to altered DGK activity, and opposing perturbations of DGK-regulated signaling produce reciprocal effects on GC B-cell accumulation while both compromise productive humoral immunity. These findings identify DGKs as critical regulators that tune lipid signaling for B-cell maturation, GC homeostasis, and effective antibody responses.
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BibTeX
@misc{xie2026diacylglycerol,
title = {{Diacylglycerol Kinases Balance DAG Signaling to Control B Cell Maturation, Germinal Center Homeostasis, and Humoral Immunity}},
author = {J. Xie and S. Zhang and W. Lee and H. Tao and Y. Pan and X. Luo and X.-P. Zhong},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756823},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756823v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Diacylglycerol Kinases Balance DAG Signaling to Control B Cell Maturation, Germinal Center Homeostasis, and Humoral Immunity
AU - J. Xie
AU - S. Zhang
AU - W. Lee
AU - H. Tao
AU - Y. Pan
AU - X. Luo
AU - X.-P. Zhong
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756823
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756823v1
AB - Diacylglycerol (DAG) is a critical second messenger downstream of the B-cell receptor (BCR), but how DAG signaling is regulated during B-cell development and humoral responses remains incompletely understood. Here, complementary gain- and loss-of-function approaches revealed stage-specific requirements for diacylglycerol kinase (DGK)-regulated signaling in B cells. Expression of the gain-of-function DGK{zeta} mutant DGK{zeta}{Delta}NLS had limited effects on early BM B-cell development but progressively impaired transitional and mature B-cell populations. DGK{zeta}{Delta}NLS attenuated BCR-induced ERK1/2 and mTOR signaling, activation, and proliferation and, when expressed in AID-expressing B cells, reduced GC B-cell survival and T-dependent IgG responses without detectably impairing GC B-cell proliferation in vivo. Conversely, combined DGK/{zeta} deficiency resulted in marked spontaneous GC B-cell expansion associated with enhanced ERK1/2, Akt, and S6 signaling and increased glucose uptake. Despite this steady-state GC expansion, DGK/{zeta}-deficient mice developed spontaneous autoreactivity and mounted impaired antigen-specific antibody responses. Thus, B-cell developmental stages exhibit differential sensitivity to altered DGK activity, and opposing perturbations of DGK-regulated signaling produce reciprocal effects on GC B-cell accumulation while both compromise productive humoral immunity. These findings identify DGKs as critical regulators that tune lipid signaling for B-cell maturation, GC homeostasis, and effective antibody responses.
ER -