biostudies-literatureUnknown5(1)Hodgson RKidney Research UKRCUK | Medical Research CouncilPeripheral tolerance prevents the initiation of damaging immune responses by autoreactive lymphocytes. While tolerogenic mechanisms are tightly regulated by antigen-dependent and independent signals, downstream pathways are incompletely understood. N-myc downstream-regulated gene 1 (NDRG1), an anti-cancer therapeutic target, has previously been implicated as a CD4⁺ T cell clonal anergy factor. By RNA-sequencing, we identified Ndrg1 as the third most upregulated gene in anergic, compared to naïve follicular, B cells. Ndrg1 is upregulated by B cell receptor activation (signal one) and suppressed by co-stimulation (signal two), suggesting that NDRG1 may be important in B cell tolerance. However, though Ndrg1^-/- mice have a neurological defect mimicking NDRG1-associated Charcot-Marie-Tooth (CMT4d) disease, primary and secondary immune responses were normal. We find that B cell tolerance is maintained, and NDRG1 does not play a role in downstream responses during re-stimulation of in vivo antigen-experienced CD4⁺ T cells, demonstrating that NDGR1 is functionally redundant for lymphocyte anergy.Communications biology1216https://www.ebi.ac.uk/biostudies/studies/S-EPMC9649591biostudies-literatureNDRG1 is induced by antigen-receptor signaling but dispensable for B and T cell self-tolerance.PMC9649591Bhandari AHodgson RCrockford TLDeobagkar-Lele MAnzilotti CBull KRWilcock MJCebrian-Serrano AKepple JDXu XCawthorne ECornall RJDavies BfalseNDRG1 is induced by antigen-receptor signaling but dispensable for B and T cell self-tolerance.Peripheral tolerance prevents the initiation of damaging immune responses by autoreactive lymphocytes. While tolerogenic mechanisms are tightly regulated by antigen-dependent and independent signals, downstream pathways are incompletely understood. N-myc downstream-regulated gene 1 (NDRG1), an anti-cancer therapeutic target, has previously been implicated as a CD4⁺ T cell clonal anergy factor. By RNA-sequencing, we identified Ndrg1 as the third most upregulated gene in anergic, compared to naïve follicular, B cells. Ndrg1 is upregulated by B cell receptor activation (signal one) and suppressed by co-stimulation (signal two), suggesting that NDRG1 may be important in B cell tolerance. However, though Ndrg1^-/- mice have a neurological defect mimicking NDRG1-associated Charcot-Marie-Tooth (CMT4d) disease, primary and secondary immune responses were normal. We find that B cell tolerance is maintained, and NDRG1 does not play a role in downstream responses during re-stimulation of in vivo antigen-experienced CD4⁺ T cells, demonstrating that NDGR1 is functionally redundant for lymphocyte anergy.2022-01-01T00:00:00Z2022 Nov2024-11-20T15:23:07.402Z2024-11-20T15:23:07.402ZS-EPMC96495913635748610.1038/s42003-022-04118-w