Differential Expression of ARG1 and MRC2 in Retinal Müller Glial Cells During Autoimmune Uveitis

Biomolecules, Journal Year: 2025, Volume and Issue: 15(2), P. 288 - 288

Published: Feb. 14, 2025

Retinal Müller glial cells (RMG) play a crucial role in retinal neuroinflammation, including autoimmune uveitis. Increasing evidence supports their function as active modulators of immune responses and potential atypical antigen-presenting (APCs). To further investigate this hypothesis, we conducted differential proteome analysis primary equine RMG from healthy controls horses with recurrent uveitis (ERU), spontaneous model This identified 310 proteins abundance. Among these, the Major Histocompatibility Complex (MHC) class II enzyme Arginase 1 (ARG1) were significantly enriched uveitis-affected horses, whereas Mannose Receptor C-type 2 (MRC2) its interactor Thrombospondin (THBS1) more abundant RMG. The detection MHC RMG, consistent previous studies, validates robustness our approach. Furthermore, identification ARG1 MRC2, together THBS1, provides new insights into immunomodulatory properties Immunohistochemical analyses confirmed proteomic findings revealed spatial distribution MRC2. MRC2 are thus markers for neuroinflammatory or physiological milieu highlight differences particularly antigen presentation.

Language: Английский

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Highlights of 2024: Cytokines and ligands modulating NK cell effector functions

Immunology and Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

In this article for the "Highlights of 2024" Series, we discuss natural killer cells, which are essential players in immune defense, with their function tightly regulated by cytokines and ligand-receptor interactions. We important recent findings that have uncovered critical regulatory pathways shaping NK cell activity.

Language: Английский

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Targeting SHP‐1‐Mediated Inhibition of STAT3 and ERK Signalling Pathways Rescues the Hyporesponsiveness of MHC‐I‐Deficient NK‐92MI

Cell Proliferation, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Natural Killer (NK) cells have shown promising prospects in 'off-the-shelf' cell therapy, particularly the NK-92 line, which can serve as a foundation for next generation of universal chimeric antigen receptor (CAR)-engineered NK products. A key strategy generating cellular products is elimination beta-2-microglobulin (B2M) gene, encodes component MHC class I molecules (MHC-I) that plays role presentation foreign antigens and 'licensing' or 'education' cells. To functionally study impacts MHC-I deficiency on NK-92, we generated B2M knockout (KO) NK-92MI (B-92) line compared multidimensional properties KO wild-type terms biological phenotypes, effector functions, transcriptomic signatures. We observed decrease activating receptors, cytokine production, cytotoxicity B-92 Further analysis signalling events revealed upregulated expression phosphorylation SHP-1 inhibited levels STAT3 ERK, thereby affecting their killing function. By knocking out (PTPN6), partially restored cytotoxic function Notably, also found CAR modification overcome hyporesponsiveness These findings will facilitate further exploration development cell-based

Language: Английский

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A potential prognostic marker for hematologic neoplasms: CD58

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: April 29, 2025

CD58 is a glycoprotein receptor widely distributed on histiocytes that binds to CD2, takes part in constituting the Immunological Synapses (IS) and activating T/NK cells. Aberrant expression of has been demonstrated exert significant impact prognosis hematological tumors, including leukemia lymphoma. Furthermore, this aberrant associated with drug resistance immune rejection CAR cell therapy. In article, we will explore future oncology by describing its function cells, immunotherapies such as

Language: Английский

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Combined CLEC2d Expression and CD58 Loss Mitigate Rejection of Allogeneic T Cells

Journal of Immunotherapy, Journal Year: 2025, Volume and Issue: 48(4), P. 127 - 137

Published: April 2, 2025

Immunogenicity of allogeneic chimeric antigen receptor (CAR) T cell therapies may preclude durable therapeutic responses and broad clinical implementation. Although genetic knockout (KO) beta-2-microglobulin (B2M) is commonly employed to abrogate HLA class I expression thereby preventing allorecognition by recipient cells, this deficiency induces missing-self natural killer (NK) cells. Here, we demonstrated that forced a membrane-bound CLEC2d, an inhibitory ligand CD161, concurrent loss CD58 (LFA-3), adhesion CD2, substantially mitigated NK against B2MKO This combination reduced in vitro cell-dependent lysis greater extent than either strategy alone increased the vivo persistence these cells after infusion into cell-replete humanized mice. Collectively, findings demonstrate convergence orthogonal genome engineering approaches effectively averts cell-driven rejection for immunotherapy.

Language: Английский

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Quadruple adenine base–edited allogeneic CAR T cells outperform CRISPR/Cas9 nuclease–engineered T cells

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(20)

Published: May 5, 2025

Genome-editing technologies have enabled the clinical development of allogeneic cellular therapies, yet optimal gene-editing modality for multiplex editing therapeutic T cell product manufacturing remains elusive. In this study, we conducted a comprehensive comparison CRISPR/Cas9 nuclease and adenine base editor (ABE) in generating chimeric antigen receptor (CAR) cells, utilizing extensive vitro vivo analyses. Both methods achieved high efficiencies across four target genes, critical mitigating graft-versus-host disease allograft rejection: TRAC or CD3E , B2M CIITA PVR . Notably, ABE demonstrated higher yields distinct off-target profiles compared to Cas9, with translocations observed exclusively Cas9-edited products. Functionally, ABE-edited CAR cells exhibited superior effector functions under continuous stimulation, including enhanced proliferative capacity increased surface expression. Transcriptomic analysis revealed that resulted reduced activation p53 DNA damage response pathways at baseline, along sustained metabolic during stress. Consistently, Assay Transposase-Accessible Chromatin using sequencing data indicated Cas9-edited, but not ABE-edited, showed enrichment chromatin accessibility peaks associated double-strand break repair pathways. preclinical leukemia model, improved tumor control extended overall survival their counterparts. Collectively, these findings position as Cas9 nucleases gene cells.

Language: Английский

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Ablation of FAS confers allogeneic CD3– CAR T cells with resistance to rejection by T cells and natural killer cells

Nature Biomedical Engineering, Journal Year: 2024, Volume and Issue: 8(12), P. 1651 - 1664

Published: Nov. 18, 2024

Language: Английский

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Hypoimmunogenic CD19 CAR-NK cells derived from embryonic stem cells suppress the progression of human B-cell malignancies in xenograft animals

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 27, 2024

Chimeric antigen receptor (CAR) engineered natural killer (NK) cells exhibit advantages such as MHC-independent recognition and strong anti-tumor functions. However, allogeneic CAR-NK derived from human tissues are heterogeneous susceptible to clearance by hosts.

Language: Английский

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Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses

The Journal of Immunology, Journal Year: 2024, Volume and Issue: 213(12), P. 1799 - 1810

Published: Dec. 2, 2024

Abstract Chimeric Ag receptor T cells derived from universal donors are susceptible to recipient immunologic rejection, which may limit their in vivo persistence and compromise treatment efficacy. In this study, we generated HLA class I–deficient by disrupting β2-microglobulin evade recognition HLA-mismatched CD8+ cells, then restored NK cell tolerance forced expression of an HLA-E single-chain receptor. We specifically report on optimized hypoimmunogenic disulfide trap HLA-E4 (dtHLA-E4) molecule that exhibited increased surface expression, enhanced inhibitory potential, abrogated CD8-dependent recognition. Our dtHLA-E4 comprised the CD4 (4) transmembrane domain truncated cytoplasmic region, as well mutations anchor I signal sequence-derived peptide. Functional comparison molecules fused different VL9 epitopes showed peptides HLA-A HLA-C allotypes maximized inhibition minimized NKG2C+ activation. Furthermore, incorporation into α3 diminished immunogenicity reducing recognition, but crucially, these left function intact. These findings demonstrate systematic construction a molecule, promises facilitate allogeneic chimeric overcoming missing-self

Language: Английский

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Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells

Molecular Therapy, Journal Year: 2024, Volume and Issue: 32(10), P. 3485 - 3503

Published: Sept. 1, 2024

Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of CAR-T may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin tacrolimus effectively mitigate allorejection HLA-mismatched immunocompetent humanized mice, extending persistence to syngeneic mouse-derived cells. In turn, genetic knockout (KO) FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted both drugs, was necessary confer CD19-specific (19CAR) robust functional resistance these immunosuppressants. FKBP1A

Language: Английский

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