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  • 1
    Online Resource
    Online Resource
    Table_1.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-12-23)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-12-23)
    Abstract: Treg therapies are being tested in clinical trials in transplantation and autoimmune diseases, however, the impact of inflammation on Tregs remains controversial. We challenged human Tregs ex-vivo with pro-inflammatory cytokines IL-6 and TNF α and observed greatly enhanced proliferation stimulated by anti-CD3 and anti-CD28 (aCD3/28) beads or CD28 superagonist (CD28SA). The cytokine-exposed Tregs maintained high expression of FOXP3 and HELIOS, demethylated FOXP3 enhancer, and low IFNγ, IL-4, and IL-17 secretion. Blocking TNF receptor using etanercept or deletion of TNF receptor 2 using CRISPR/Cas9 blunted Treg proliferation and attenuated FOXP3 and HELIOS expression. These results prompted us to consider using CD28SA together with IL-6 and TNF α without aCD3/28 beads (beadless) as an alternative protocol for therapeutic Treg manufacturing. Metabolomics profiling revealed more active glycolysis and oxidative phosphorylation, increased energy production, and higher antioxidant potential during beadless Treg expansion. Finally, beadless expanded Tregs maintained suppressive functions in vitro and in vivo . These results demonstrate that human Tregs positively respond to proinflammatory cytokines with enhanced proliferation without compromising their lineage identity or function. This property can be harnessed for therapeutic Treg manufacturing.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.783282
    DOI: 10.3389/fimmu.2021.783282.s001
    DOI: 10.3389/fimmu.2021.783282.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 2
    Online Resource
    Online Resource
    DataSheet_1.docx
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-9-20)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-9-20)
    Abstract: Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-ζ signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR + TCR deficient human Tregs maintained both Treg phenotype and function in vitro . Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR + TCR deficient Tregs did not impair the function of these HLA-A2 + islets, whereas similarly engineered A2-CAR + TCR deficient CD4 + conventional T cells rejected the islets in less than 2 weeks. A2-CAR + TCR deficient Tregs delayed graft- versus -host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2021.686439
    DOI: 10.3389/fimmu.2021.686439.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 3
    Online Resource
    Online Resource
    The dichotomous outcomes of TNFα signaling in CD4+ T cells
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-11-16)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-11-16)
    Abstract: TNFa blocking agents were the first-in-class biologic drugs used for the treatment of autoimmune disease. Paradoxically, however, exacerbation of autoimmunity was observed in some patients. TNFa is a pleiotropic cytokine that has both proinflammatory and regulatory effects on CD4 + T cells and can influence the adaptive immune response against autoantigens. Here, we critically appraise the literature and discuss the intricacies of TNFa signaling that may explain the controversial findings of previous studies. The pleiotropism of TNFa is based in part on the existence of two biologically active forms of TNFa, soluble and membrane-bound, with different affinities for two distinct TNF receptors, TNFR1 and TNFR2, leading to activation of diverse downstream molecular pathways involved in cell fate decisions and immune function. Distinct membrane expression patterns of TNF receptors by CD4 + T cell subsets and their preferential binding of distinct forms of TNFα produced by a diverse pool of cellular sources during different stages of an immune response are important determinants of the differential outcomes of TNFa-TNF receptor signaling. Targeted manipulation of TNFa-TNF receptor signaling on select CD4 + T cell subsets may offer specific therapeutic interventions to dampen inflammation while fortifying immune regulation for the treatment of autoimmune diseases.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2022.1042622
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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