Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti-OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti-OX40L on immunosuppression in keyhole limpet hemocyanin-immunized C57BL/6J mice. In vitro treatment of anti-OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti-OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti-dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T-follicular helper cells (Tfh). In keyhole limpet hemocyanin-immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti-OX40L group. Anti-OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti-OX40L downregulated CD4+ T-cell differentiation into Th1 and Tfh cells and upregulated CD4+ T-cell differentiation into regulatory T cells in vitro. Furthermore, anti-OX40L inhibited toll-like receptor 7-mediated differentiation of antibody-secreting cells and antibody production through the regulation of the SPIB-BLIMP1-XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE.
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Objectives: OX40 ligand (OX40L) locus genetic variants have relationships with the risk for systemic lupus erythematosus (SLE), OX40L blockade has been shown to ameliorate renal damage and suppress autoantibody production in NZB/W F1 mice. However, it is unclear how OX40L blockade delays lupus phenotype. Methods In present study, we examined the impact of blocking OX40L using anti-OX40L in the MRL/lpr murine model of lupus. Mice were sorted into 3 groups with 9 ~ 11 mice per group as follows: IgG treatment, Cyclophosphamide (CTX) treatment, and anti-OX40L treatment. Treated mice were harvested, and samples of serum, kidney, and spleen were collected for outcome evaluation. Next, we investigated the impact of anti-OX40L on immunosuppression in KLH-immunized C57BL/6J mice aged 8 weeks through the detection of serum immunoglobulins (Igs) and splenocyte flow cytometry. In vitro treatment of anti-OX40L in CD4 + T and CD19 + B cells were used for exploring the roles of OX40L in SLE pathogenesis. Results Anti-OX40L delayed disease progression in MRL/lpr mice, accompanied by decreased production of anti-dsDNA, proteinuria, and Ig deposition in kidney, as well as lower frequencies of Th1 and Tfh cells in the spleen. Compared to the IgG group, anti-OX40L was found to up-regulate polyclonal CD4 + T cell differentiation into Tregs in vitro. In KLH-immunized mice, decreased levels of Igs, and plasmablast cells were observed in anti-OX40L group. Blocking OX40/OX40L signaling also inhibited TLR7-mediated differentiation of antibody secreting cells (ASCs) and production of antibody through the up-regulation of SPI-B, IRF8, and PAX5, and down-regulation of Xbp-1 in B cells in vitro . Conclusion Together, these results propose OX40L as a promising therapeutic target for SLE.

Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B-cell hyperplasia model (Cγ1-Cre Blimp1fl/fl ) through immune-competent mice. Lymphoma cells were identified as clonal TCRβ+ T-helper cells expressing T-follicular helper markers. We also observed coincident B-cell activation and development of a de novo B-cell lymphoma in the model, reminiscent of B-cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high-risk "GATA3" subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human-relevant oncogenic β-catenin mutation possibly involved in T-cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T-cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL.
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.