Immunologic Applications of Conditional Gene Modification Technology in the Mouse

Sharma, Suveena; Zhu, Jinfang

doi:10.1002/0471142735.im1034s105

Cited by 28 publications

(21 citation statements)

References 83 publications

(108 reference statements)

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“…CD4 (Cre) is expressed in late double-negative to double-positive stages that leading to deletion of floxed genes in both CD4 and CD8 T cells. 28,29 Therefore, Sirt-1 fl/fl CD4Cre 1 mice have Sirt-1 deficiency in both CD4 and CD8 T cells.…”

Section: Sirt-1 Regulates T-cell Proliferation Th1 Differentiation mentioning

confidence: 99%

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Daenthanasanmak¹,

Iamsawat²,

Chakraborty

et al. 2019

Blood

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K E Y P O I N T S l Deficiency of Sirt-1 reduces T-cell pathogenicity in GVHD by enhancing p53 acetylation in T cells and promoting iTreg stability. l Treatment with a Sirt-1 inhibitor reduces Tfh generation, B-cell activation, and plasma cell differentiation during cGVHD development.Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Sirtuin-1 (Sirt-1) plays a crucial role in various biological processes including cellular senescence, metabolism, and inflammatory responses. Sirt-1 deacetylation regulates different transcription factors that are important for modulating immune responses. In the current study, we addressed the role of Sirt-1 in GVHD induction by employing Sirt-1 conditional knockout mice as well as a pharmacological Sirt-1 inhibitor. Using major histocompatibility complex (MHC)-mismatched and MHC-matched murine BMT models, we found that Sirt-1 2/2 T cells had a reduced ability to induce acute GVHD (aGVHD) via enhanced p53 acetylation. Sirt-1-deficient T cells also promoted induced regulatory T cell (iTreg) differentiation and inhibited interferon-g production after allo-BMT. Sirt-1 deletion in iTregs increased Foxp3 stability and restrained iTreg conversion into pathogenic T cells. Furthermore, we found that administration with a Sirt-1 inhibitor, Ex-527, significantly improved recipient survival and clinical scores, with no signs of tumor relapse. These results indicate that Sirt-1 inhibition can attenuate GVHD while preserving the graft-versus-leukemia effect. Consistently, Sirt-1-deficient T cells also displayed a remarkably reduced ability to induce chronic GVHD (cGVHD). Mechanistic studies revealed that Sirt-1 deficiency in T cells enhanced splenic B-cell reconstitution and reduced follicular T helper cell development. Sirt-1 deficiency in T cells modulated donor B-cell responses reducing both B-cell activation and plasma cell differentiation. In addition, therapeutic Sirt-1 inhibition could both prevent cGVHD and reduce established cGVHD. In conclusion, Sirt-1 is a promising therapeutic target for the control of aGVHD and cGVHD pathogenesis and possesses high potential for clinical application. (Blood. 2019;133 (3):266-279) Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic bone marrow transplantation (allo-BMT). Acute GVHD (aGVHD) is distinguished by uncontrolled activation, migration, and proliferation of allogeneic donor T cells, as well as their production of pro-inflammatory 266 blood®

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Section: Sirt-1 Regulates T-cell Proliferation Th1 Differentiation mentioning

confidence: 99%

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Daenthanasanmak¹,

Iamsawat²,

Chakraborty

et al. 2019

Blood

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“…The Cre-loxP system allows for conditional deletion of genes in specific cell lineages (Sharma and Zhu, 2014). In this system, two 34-bp loxP sites are inserted on either side of a gene or exon, which is then said to be “floxed”.…”

Section: Mouse Models For Studying Dendritic Cellsmentioning

confidence: 99%

Functions of Murine Dendritic Cells

2016

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Dendritic cells (DCs) play critical roles in activating innate immune cells and initiating adaptive immune responses. The functions of DCs were originally obscured by their overlap with other mononuclear phagocytes, but new mouse models have allowed for the selective ablation of subsets of DCs and have helped to identify their non-redundant roles in the immune system. These tools have elucidated the functions of DCs in host defense against pathogens, autoimmunity, and cancer. This review will describe the mouse models generated to interrogate the role of DCs, and will discuss how their use has progressively clarified our understanding of the unique functions of DC subsets.

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“…This might be due to an incomplete ablation of endogenous NFATc1 in splenic CD8 + T cells of dlck-cre x Nfatc1 flx/flx mice. A deletion efficiency of approximately 80% has been reported for the dlck-cre line in CD8 + T cells, whereas a markedly higher efficiency rate was detected for the murine CD4-cre line ( 33 ).…”

Section: Resultsmentioning

confidence: 96%

The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts

et al. 2018

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The immune suppressants cyclosporin A (CsA) and tacrolimus (FK506) are used worldwide in transplantation medicine to suppress graft rejection. Both CsA and FK506 inhibit the phosphatase calcineurin (CN) whose activity controls the immune receptor-mediated activation of lymphocytes. Downstream targets of CN in lymphocytes are the nuclear factors of activated T cells (NFATs). We show here that the activity of NFATc1, the most prominent NFAT factor in activated lymphocytes supports the acute rejection of heterotopic heart allografts. While ablation of NFATc1 in T cells prevented graft rejection, ectopic expression of inducible NFATc1/αA isoform led to rejection of heart allografts in recipient mice. Acceptance of transplanted hearts in mice bearing NFATc1-deficient T cells was accompanied by a reduction in number and cytotoxicity of graft infiltrating cells. In CD8+ T cells, NFATc1 controls numerous intracellular signaling pathways that lead to the metabolic switch to aerobic glycolysis and the expression of numerous lymphokines, chemokines, and their receptors, including Cxcr3 that supports the rejection of allogeneic heart transplants. These findings favors NFATc1 as a molecular target for the development of new strategies to control the cytotoxicity of T cells upon organ transplantation.

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Immunologic Applications of Conditional Gene Modification Technology in the Mouse

Cited by 28 publications

References 83 publications

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice

Functions of Murine Dendritic Cells

The Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts

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