Ripk1 plays an important role as a regulator of programmed cell death processes such as apoptosis and necroptosis and is involved in initiating pro-inflammatory NF-κB signaling. Immune tolerance depends on the proper function and homeostasis of regulatory T (Treg) cells. Here, we show that specific ablation of Ripk1 in Treg cells leads to systemically reduced Treg cell numbers resulting in spontaneous whole-body pathology. Using chimeric mice that allowed us to study Treg cells in the absence of inflammatory conditions, we observed a competitive disadvantage in vivo of Ripk1-deficient compared to Ripk1-proficient Treg cells. Furthermore, single-cell RNA sequencing revealed that Ripk1 is required for the maintenance of the effector Treg cell transcriptional signature, which is essential to prevent immune dysregulation. To overcome the limitation of low cell numbers in the chimeric mice, we isolated Treg cells from mice, in which Ripk1 could be deleted in a tamoxifen-inducible manner. Despite the strong reduction detected in Ripk1-deficient Treg cells of the chimeric mice, we did not observe impaired viability by the sole absence of Ripk1 in Treg cells from the inducible system. Of note, we observed reduced viability of activated Ripk1-deficient Treg cells in the presence of TNF. Together, these findings highlight the fundamental role of Ripk1 in maintaining immune homeostasis by preserving the highly suppressive effector Treg cells.
© 2025. The Author(s).

Accumulating evidence suggests that Gα13 signaling by G protein-coupled receptors negatively regulate B cell function. We report here that lysophosphatidylserine (LysoPS), an emerging immunoregulatory lysophospholipid, is produced upon B cell activation and suppresses B cell adhesive properties via its Gα13-coupled receptors, LPS2 and LPS2L. B cell activation in vitro markedly increased the LysoPS level thereby inhibiting cell aggregation in a LysoPS receptor-dependent manner. In T cell-dependent antigen immunization and asthma models, LPS2/2L double knock-out mice exhibited increased B cell number with early and enhanced formation of germinal center (GC) and tertiary lymphoid structures (TLS)-like structures, in addition to an elevated antibody level and worsened conditions. We thus propose a novel regulatory mechanism for lymphocyte aggregation in which LysoPS on B cells acts in an autocrine/paracrine fashion to inhibit GC and TLS formation by disrupting B cell-B cell or B cell-T cell interactions via Gα13 signaling.
© 2025 The Authors. Published by Elsevier Inc.

The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses.
Copyright © 2024 Elsevier Inc. All rights reserved.

Lung-resident memory B cells (lung-BRMs) differentiate into plasma cells after reinfection, providing enhanced pulmonary protection. Here, we investigated the determinants of lung-BRM differentiation upon influenza infection. Kinetic analyses revealed that influenza nucleoprotein (NP)-specific BRMs preferentially differentiated early after infection and required T follicular helper (Tfh) cell help. BRM differentiation temporally coincided with transient interferon (IFN)-γ production by Tfh cells. Depletion of IFN-γ in Tfh cells prevented lung-BRM differentiation and impaired protection against heterosubtypic infection. IFN-γ was required for expression of the transcription factor T-bet by germinal center (GC) B cells, which promoted differentiation of a CXCR3+ GC B cell subset that were precursors of lung-BRMs and CXCR3+ memory B cells in the mediastinal lymph node. Absence of IFN-γ signaling or T-bet in GC B cells prevented CXCR3+ pre-memory precursor development and hampered CXCR3+ memory B cell differentiation and subsequent lung-BRM responses. Thus, Tfh-cell-derived IFN-γ is critical for lung-BRM development and pulmonary immunity, with implications for vaccination strategies targeting BRMs.
Copyright © 2023 Elsevier Inc. All rights reserved.

Glioblastoma (GBM) is the deadliest brain malignancy without effective treatments, and novel effective treatments are urgently needed. B cell lymphoma 6 (BCL6) is a transcription factor that stops cell death in response to DNA damage, primarily through repressing transcription of DNA damage response genes. Here, we identify BCL6 as a lynchpin in GBM, BCL6 expression was increased in GBM compared with normal cells and associated with GBM patients’ poor survival. Silencing of BCL6 additionally affected GBM cell proliferation and trigger cellular damage. Furthermore, we report the identification of WK499, a novel small-molecule inhibitor of BCL6. WK499 inhibited the growth of GBM cells by inhibiting BCL6 to activate p53-related signaling pathways, importantly, WK499 impeded significantly inhibition the growth of GBM cells both in vitro and in vivo. meanwhile, WK499 and TMZ Combination medication significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. In summary, our findings reveal a crucial role of BCL6 in GBM and suggest BCL6 as a therapeutic target for the treatment of this intractable disease.