JAK Inhibitors and B Cell Function: A Comparative Study of Their Impact on Plasma Cell Differentiation, Cytokine Production, and Naïve B Cell ActivationHuang, de Vries, Sharma
et alEur J Immunol (2025) 55 (3), e202451437
Abstract: B cells play a crucial role in autoimmune diseases, as evidenced by autoantibody responses and the effectiveness of B cell-targeted therapies. Janus kinase inhibitors (JAKi), which target downstream signaling of cytokine receptors, are potent rheumatic disease-modifying drugs. However, besides reducing inflammation, JAKi may impact the adaptive immune system. In this study, we examined the effects of JAKi on B-cell function using in vitro cultures and multiparameter flow cytometry. The results show a JAKi-mediated reduction in plasma cell differentiation, primarily by inhibition of memory B-cell stimulation and proliferation. JAKi exposure resulted in stalling R848, IL-2, and IL-21 stimulated B cells in an intermediate activated state with elevated naïve cells displaying increased expression of CXCR5, CD71, CD22, and CD20. In addition, the data demonstrate a moderate JAKi-mediated reduction of B cell TNF and IL-8 cytokine expression following stimulation. Importantly, the efficacy varied greatly between drugs; tofacitinib and upadacitinib (pan JAKi; JAK1i) exhibited the strongest impact, while baricitinib (JAK1/JAK2i) showed donor-dependent variation, and filgotinib (JAK1i) had no effect. All JAKi, except filgotinib, inhibited IL-2 or IL-21-induced STAT3 phosphorylation. Still, filgotinib demonstrated similar inhibition of phospho-STAT5 as other JAKi following IL-21. These findings underscore the therapeutic impact of JAKi through the modulation of B-cell functions.© 2025 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.
Gene-modified NK cells expressing CD64 and preloaded with HIV-specific BNAbs target autologous HIV-1-infected CD4+ T cells by ADCCTomescu, Ochoa-Ortiz, Lu
et alJ Immunol (2025) 214 (2), 253-264
Abstract: Natural killer (NK) cells can efficiently mediate antibody-dependent cellular cytotoxicity (ADCC) of antibody coated target cells via the low-affinity Fc-receptor, CD16, but cannot retain antibodies over time. To increase antibody retention and facilitate targeted ADCC, we genetically modified human NK cells with the high-affinity Fc receptor, CD64, so that we could preload them with HIV-specific broadly neutralizing antibodies (BNAbs) and enhance their capacity to target HIV-infected cells via ADCC. Purified NK cells from the peripheral blood of control donors or persons living with HIV were activated with interleukin (IL)-2/IL-15/IL-21 cytokines and transduced with a lentivirus encoding CD64. High levels of CD64 surface expression were maintained for multiple weeks on NK cells and CD64-transduced NK cells were phenotypically similar to control NK cells with strong expression of CD56, CD16, NKG2A, NKp46, CD69, HLA-DR, CD38, and CD57. CD64-transduced NK cells exhibited significantly greater capacity to bind HIV-specific BNAbs in short-term antibody binding assay as well as retain the BNAbs over time (1-wk antibody retention assay) compared with control NK cells only expressing CD16. BNAb-preloaded CD64-transduced NK cells showed a significantly enhanced capacity to mediate ADCC against autologous HIV-1-infected CD4+ primary T cells in both a short-term 4 h degranulation assay as well as a 24 h HIV p24 HIV elimination assay when compared with control NK cells. A chimeric CD64 enhanced NK cell strategy (NuKEs [NK Enhancement Strategy]) retaining bound HIV-specific BNAbs represents a novel autologous primary NK cell immunotherapy strategy against HIV through targeted ADCC.© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
Age-Associated B Cells in Autoimmune Diseases: Pathogenesis and Clinical ImplicationsXie, Chen, Gao
et alClin Rev Allergy Immunol (2025) 68 (1), 18
Abstract: As a heterogeneous B cell subset, age-associated B cells (ABCs) exhibit distinct transcription profiles, extrafollicular differentiation processes, and multiple functions in autoimmunity. TLR7 and TLR9 signals, along with IFN-γ and IL-21 stimulation, are both essential for ABC differentiation, which is also regulated by chemokine receptors including CXCR3 and CCR2 and integrins including CD11b and CD11c. Given their functions in antigen uptake and presentation, autoantibody and proinflammatory cytokine secretion, and T helper cell activation, ABCs display potential in the prognosis, diagnosis, and therapy for autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, neuromyelitis optica spectrum disorders, and ankylosing spondylitis. Specifically targeting ABCs by inhibiting T-bet and CD11c and activating CD11b and ARA2 represents potential therapeutic strategies for SLE and RA. Although single-cell sequencing technologies have recently revealed the heterogeneous characteristics of ABCs, further investigations to explore and validate ABC-target therapies are still warranted.© 2025. The Author(s).
Chimeric cytokine receptor TGF-β RⅡ/IL-21R improves CAR-NK cell function by reversing the immunosuppressive tumor microenvironment of gastric cancerRen, Xue, Hui
et alPharmacol Res (2025) 212, 107637
Abstract: Gastric cancer remains a significant global health burden, characterized by regional variations in incidence and poor survival prospects in advanced stages. Natural killer (NK) cells play a crucial role in the body's anti-cancer defense, and chimeric antigen receptor (CAR)-NK cell therapy is gaining attention as a cutting-edge and promising treatment method. This study aims to tackle the challenge of TGF-β-mediated tumor immune evasion within the immunosuppressive tumor microenvironment by designing a novel chimeric cytokine receptor TRII/21 R, which consists of extracellular domains of TGF-β receptor II (TRII) and transmembrane and intracellular domains of IL-21 receptor (21 R) and can convert the immunosuppressive signal from TGF-β in the tumor microenvironment (TME) into an NK cell activation signal through the IL-21R-STAT3 pathway. We successfully constructed NKG2D-CAR-NK cells expressing TRII/21 R and demonstrated strong anti-tumor activity against cancer cells both in vitro and in vivo. The co-expression of TRII/21 R in CAR-NK cells enhanced the cytotoxicity, promoted proliferation and survival capabilities, and reduced the expression of exhaustion markers. In the xenograft mouse model, TRII/21R-CAR-NK cells significantly inhibited tumor growth and improved the survival rate of tumor-bearing mice compared to the mice receiving control CAR-NK cells. Additionally, TRII/21 R co-expression enhanced NK cells' infiltration, activation, and persistence within the tumor, indicating a robust anti-tumor response mediated by the JAK-STAT3 signaling pathway. This study underscores the therapeutic potential of TRII/21R-modified CAR-NK cells as a breakthrough strategy for combating cancer.Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.
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