Hidden Caveat of Inducible Cre Recombinase

Kurachi, Makoto; Ngiow, Shin Foong; Kurachi, Junko; Chen, Zeyu; Wherry, E. John

doi:10.1016/j.immuni.2019.09.010

Cited by 28 publications

(13 citation statements)

References 5 publications

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“…To further delineate the cell-autonomous role of TNFR2 in Treg cell biology, we generated mice with conditional ablation of TNFR2 in Treg cells by crossing mice expressing the CRErecombinase in Treg cells (Foxp3 Cre ) with mice carrying floxed Tnfrsf1b alleles (Tnfrsf1b fl ). It was critical to compare these Foxp3 Cre Tnfrsf1b fl (hereafter named conditional knock-out or 'cKO') mice to their proper controls, the Foxp3 Cre mice, because of putative toxic effect of Cre expression, as recently reported (19,20). As expected, Treg cells of cKO mice had complete ablation of TNFR2 expression (Fig.…”

Section: Tnfr2 Signaling In Treg Cells Mediates Disease Suppression During Overt Cns Inflammationmentioning

confidence: 75%

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

Ronin

Pouchy

Khosravi

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell–mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.

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Section: Tnfr2 Signaling In Treg Cells Mediates Disease Suppression During Overt Cns Inflammationmentioning

confidence: 75%

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

Ronin

Pouchy

Khosravi

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…To directly test the effects of increased nuclear T-bet on T cell activation, naive P14 TCR transgenic CD8 T cells specific for LCMV D b GP 33-41 were retrovirally transduced with a recombinant version of T-bet fused to the estrogen receptor (ER) by using a GFP reporter to identify transduced cells. The T-bet-ER protein will be retained in the cytoplasm until treatment with tamoxifen that will cause translocation to the nucleus (Kao et al, 2011;Kurachi et al, 2019;unpublished data). T-bet-ER-GFP-retroviral (RV)-transduced P14 cells were adoptively transferred into congenic LCMV-clone-13-infected mice (Figure 6A).…”

Section: Blocking the Pd-1 Pathway Re-engages T-bet Transcriptional Circuits During Chronic Lcmv Infectionmentioning

confidence: 99%

Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells

et al. 2021

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“…A critical question for investigating communication networks in vivo relates to the specific sender-respective responder cell types and tissue-specific metabolic pathways. Widely used genetic systems like the Cre- lox P system are valuable genetic systems to specifically ablate genes in a cell-type-specific manner, but come with certain limitations as discussed elsewhere ( Becher et al., 2018 ; Kurachi et al., 2019 ). Recombinant adeno-associated viral (AAV) vectors pose a versatile alternative to specifically manipulate gene expression in a wide range of tissues in vivo ( Srivastava, 2016 ).…”

Section: Technological Approaches To Study Systemic Immunometabolismmentioning

confidence: 99%

Systemic Immunometabolism: Challenges and Opportunities

2020

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Over the past 10 years, the field of immunometabolism made great strides to unveil the crucial role of intracellular metabolism in regulating immune cell function. Emerging insights into how systemic inflammation and metabolism influence each other provide a critical additional dimension on the organismal level. Here, we discuss the concept of systemic immunometabolism and review the current understanding of the communication circuits that underlie the reciprocal impact of systemic inflammation and metabolism across organs in inflammatory and infectious diseases, as well as how these mechanisms apply to homeostasis. We present current challenges of systemic immunometabolic research, and in this context, highlight opportunities and put forward ideas to effectively explore organismal physiological complexity in both health and disease.

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Hidden Caveat of Inducible Cre Recombinase

Cited by 28 publications

References 5 publications

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells

Systemic Immunometabolism: Challenges and Opportunities

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