In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4
            <sup>+</sup>
            T
            <sub>H</sub>
            1 cell response

Galy, Aurélien Sutra Del; Menegatti, Silvia; Fuentealba, Jaime; Lucibello, Francesca; Perrin, Laëtitia; Helft, Julie; Darbois, Aurélie; Saitakis, Michael; Tosello, Jimena; Rookhuizen, Derek C.; Deloger, Marc; Gestraud, Pierre; Socié, Gèrard; Amigorena, Sebastián; Lantz, Olivier; Menger, Laurie

doi:10.1126/sciimmunol.abe8219

Cited by 39 publications

(33 citation statements)

References 83 publications

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“…[ 34 ] SOCS1 was also identified as a checkpoint for antigen‐experienced CD4 + T cell expansion. [ 35 ] However, the role of SOCS1 in another immune‐related disorder, GVHD, has not been elucidated. Our clinical data showed that a low expression level of SOCS1 in T cells from patients was correlated with GVHD occurrence after HSCT.…”

Section: Discussionmentioning

confidence: 99%

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Guo

Wang

et al. 2022

Advanced Science

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Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Inflammatory signaling pathways promote T-cell activation and are involved in the pathogenesis of GVHD. Suppressor of cytokine signaling 1 (SOCS1) is a critical negative regulator for several inflammatory cytokines. However, its regulatory role in T-cell activation and GVHD has not been elucidated. Multiomics analysis of the transcriptome and chromatin structure of granulocyte-colony-stimulating-factor (G-CSF)-administered hyporesponsive T cells from healthy donors reveal that G-CSF upregulates SOCS1 by reorganizing the chromatin structure around the SOCS1 locus. Parallel in vitro and in vivo analyses demonstrate that SOCS1 is critical for restraining T cell activation. Loss of Socs1 in T cells exacerbates GVHD pathogenesis and diminishes the protective role of G-CSF in GVHD mouse models. Further analysis shows that SOCS1 inhibits T cell activation not only by inhibiting the colony-stimulating-factor 3 receptor (CSF3R)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, but also by restraining activation of the inflammasome signaling pathway. Moreover, high expression of SOCS1 in T cells from patients correlates with low acute GVHD occurrence after HSCT. Overall, these findings identify that SOCS1 is critical for inhibiting T cell activation and represents a potential target for the attenuation of GVHD.

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Section: Discussionmentioning

confidence: 99%

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Guo

Wang

et al. 2022

Advanced Science

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“…Furthermore, SOCS-1 polymorphisms have been associated with a rapid HIV progression rate [ 92 ]. Recently, in in vivo genome-wide CRISPR screens, SOCS1 was identified as “a major non-redundant checkpoint imposing a brake on CD4+ T-cell proliferation,” which promotes HIV-1 replication in infected cells [ 93 ]. This is in agreement with the brief, robust, but transient ISG response observed in the HESN cells, suggesting that SOCS-1 may be another key molecule enabling the HESN phenotype.…”

Section: Discussionmentioning

confidence: 99%

Transient Increases in Inflammation and Proapoptotic Potential Are Associated with the HESN Phenotype Observed in a Subgroup of Kenyan Female Sex Workers

Gluchowski

Yu²,

Abrenica

et al. 2022

Viruses

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Interferon (IFN) -stimulated genes (ISGs) are critical effectors of IFN response to viral infection, but whether ISG expression is a correlate of protection against HIV infection remains elusive. A well-characterized subcohort of Kenyan female sex workers, who, despite being repeatedly exposed to HIV-1 remain seronegative (HESN), exhibit reduced baseline systemic and mucosal immune activation. This study tested the hypothesis that regulation of ISGs in the cells of HESN potentiates a robust antiviral response against HIV. Transcriptional profile of a panel of ISGs with antiviral function in PBMC and isolated CD4+ T cells from HESN and non-HESN sex worker controls were defined following exogenous IFN-stimulation using relative RT-qPCR. This study identified a unique profile of proinflammatory and proapoptotic ISGs with robust but transient responses to exogenous IFN-γ and IFN-α2 in HESN cells. In contrast, the non-HESN cells had a strong and prolonged proinflammatory ISG profile at baseline and following IFN challenge. Potential mechanisms may include augmented bystander apoptosis due to increased TRAIL expression (16-fold), in non-HESN cells. The study also identified two negative regulators of ISG induction associated with the HESN phenotype. Robust upregulation of SOCS-1 and IRF-1, in addition to HDM2, could contribute to the strict regulation of proinflammatory and proapoptotic ISGs in HESN cells. As reducing IRF-1 in the non-HESN cells resulted in the identified HESN ISG profile, and decreased HIV susceptibility, the unique HESN ISG profile could be a correlate of protection against HIV infection.

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“…Of note, for in vivo screening approach, we have injected 10 to 12 × 10 6 /100 μL GW-KO T cells per mouse intravenously. 8 We strongly recommend to have at least 100 copies of each sgRNA per mouse.…”

Section: Expected Outcomesmentioning

confidence: 99%

“…Even if we and others have successfully engineered murine T cells using lentiviruses CRISPR construct, 8 , 11 the delivery of genes into murine T cells is much easier using retroviral constructs. This protocol allows to efficiently perform GW-KO CRISPR screens in murine T cells but is limited by (I) the delivery challenge of Cas9, which is overcome using Cas-expressing mice, (II) the required activation of T cells for retroviral transduction, 12 (III) the requirement of selection/enrichment (puromycin or congenic marker) for transduced T cells at low MOI.…”

Section: Limitationsmentioning

confidence: 99%

Optimized protocol to generate genome-wide inactivated Cas9-expressing murine T cells

2023

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In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4 ⁺ T _H 1 cell response

Abstract: Inactivation of SOCS1 optimizes adoptive T cell therapy including human CAR-T cell composition and efficacy.

Cited by 39 publications

References 83 publications

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Transient Increases in Inflammation and Proapoptotic Potential Are Associated with the HESN Phenotype Observed in a Subgroup of Kenyan Female Sex Workers

Optimized protocol to generate genome-wide inactivated Cas9-expressing murine T cells

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In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4 + T H 1 cell response

Abstract: Inactivation of SOCS1 optimizes adoptive T cell therapy including human CAR-T cell composition and efficacy.

Cited by 39 publications

References 83 publications

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Multiomics Analysis Identifies SOCS1 as Restraining T Cell Activation and Preventing Graft‐Versus‐Host Disease

Transient Increases in Inflammation and Proapoptotic Potential Are Associated with the HESN Phenotype Observed in a Subgroup of Kenyan Female Sex Workers

Optimized protocol to generate genome-wide inactivated Cas9-expressing murine T cells

Contact Info

Product

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In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4 ⁺ T _H 1 cell response