GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans

Yao, Yikun; Jiang, Ping; Chao, Brittany; Çağdaş, Deniz; Kubo, Shunsuke; Balasubramaniyam, Arasu; Yu, Zhang; Shadur, Bella; NaserEddin, Adeeb; Folio, Les; Schwarz, Benjamin; Bohrnsen, Eric; Zheng, Lixin; Lynberg, Matthew; Gottlieb, Simone; Leney-Greene, Michael; Park, Ann Y; Tezcan, İlhan; Akdoğan, Ali; Göçmen, Rahşan; Önder, Sevgen; Rosenberg, Avi; Soilleux, Elizabeth; Johnson, Errin; Jackson, Peter K.; Demeter, János; Chauvin, Samuel D.; Paul, Fabian; Selbach, Matthias; Bulut, Haydar; Clatworthy, Menna R.; Tuong, Zewen Kelvin; Zhang, Hanlin; Stewart, Benjamin J; Bosio, Catharine M.; Stepensky, Polina; Clare, Simon; Ganesan, Sundar; Pascall, John C.; Daumke, Oliver; Butcher, Geoffrey W.; McMichael, Andrew J.; Simon, Anna Katharina

doi:10.1084/jem.20201405

Cited by 7 publications

(6 citation statements)

References 89 publications

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“…2 A–C ). Although the immunologic role of GIMAPs is not well defined, they define stages of T cell development, survival, and cell identity ( 26 , 27 ) and have been reported to be associated with T cell regulatory function ( 28 ) .…”

Section: Resultsmentioning

confidence: 99%

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19

Moreira

Gauthier

Murphy

et al. 2023

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

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T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 μg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7 + effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1 , and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7 , and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

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Section: Resultsmentioning

confidence: 99%

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19

Moreira

Gauthier

Murphy

et al. 2023

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

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“…5C). Although the immunologic role of GIMAPs is not well de ned, they de ne stages of Tcell development, survival and cell identity 31,32 and have been reported to be associated with T cell regulatory function 33 .…”

Section: Resultsmentioning

confidence: 99%

Nasal anti-CD3 mAb (Foralumab) dampens CD3+ T effector function and decreases NKG7 in COVID-19 through a mechanism involving GIMAP-7 and TGFb1

Moreira

Gauthier

Murphy

et al. 2022

Preprint

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T cells are present in early stages of the SARS-CoV-2 infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully humanized anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using RNA-sequencing and serum proteomics, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100ug/day) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab treated subjects and NGK7+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1, and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes and B cells in subjects treated with Foralumab. In addition to the downregulation of effector function, an increase in TGFb1 gene expression in cell types with known effector function was observed in Foralumab treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases and TGF-b1 signaling, was downregulated in Foralumab treated individuals. TGFb1, GIMAP7 and NKG7 transcriptomic changes observed in Foralumab treated COVID-19 subjects was also observed in healthy volunteers, MS subjects and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.

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“…Previous studies have shown that Gimap6-/-lymphocytes in humans and mice had an autophagic defect, resting T cells have low basal autophagy that was upregulated by activation 19 . GIMAP6 was closely related to the occurrence of autophagy.…”

Section: Discussionmentioning

confidence: 95%

“…As a homologue of autophagy gene 8 (ATG8), GABARAPL2 co-recruits autophagosomes with GIMAP6 to play a role during autophagy. GIMAP6 deficiency resulted in defective autophagy in T cells and interruption of GIMAP7 and GABARAPL2 interactions 19 . Another research manifested that in CD4 + T cells from Gimap6 -/-mice, there was an extremely increase of mitochondrial/cytoplasmic volume and numbers of autophagosomes, while T cells remained in the normal state and can be effectively activated in vitro to produce T-cell-dependent antibodies 20 .…”

Section: Introductionmentioning

confidence: 99%

Investigation and verification of GAMAP6 as a robust biomarker for prognosis and tumor immunity in lung adenocarcinoma

Chen

Zhou

et al. 2023

Preprint

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Background and aim: It has been reported GIMAP6 was crucial for autophagy. But it is unknown the role of GIMAP6 in occurrence and tumor-immunity of lung adenocarcinoma. Methods: Comprehensive analyses for datasets from TCGA and GTEx databases were conducted by R software. Basic experiments including RT-qPCR, CCK-8 assays, colony formation assay and transwell assays were applied to explore the role of GIMAP6 in vivo and vitro. Prognostic features and GIMAP6 were applied to construct nomogram. Potential mechanism of GIMAP6 in lung adenocarcinoma was investigated by GO, KEGG and GESA. The correlation between GIMAP6 and immune landscape has also been explored using scRNA sequencing datasets from Timer 2.0 and TISCH. Results: The OS and DSS of lung adenocarcinoma patients with high GIMAP6 expression was better than that with low GIMAP6 expression. The nomogram based on T stage, N stage, and GIMAP6 had predictive significance for prognosis, which was identified by ROC and calibration curve. Functional enrichment analysis suggested that GIMAP6 was mainly involved in T-cell receptor signaling pathway, chemokine signaling pathway, cytokine and cytokine receptor interaction. Single cell sequencing and TIMER2.0 analysis illustrated that GIMAP6 was positively correlated with the infiltration of immune cells and immune-relate molecules including CTLA4, PD-L1, and TIGIT. Basic experiments confirmed the role of GIMAP6 in the proliferation, invasion and migration of lung adenocarcinoma cells. Conclusion: We confirmed that GIMAP6 was an effective prognostic molecule and involved in the regulation of the immune microenvironment of lung adenocarcinoma, which may become a predictor for the efficacy of immunotherapy.

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GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans

Cited by 7 publications

References 89 publications

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19

Nasal administration of anti-CD3 mAb (Foralumab) downregulates NKG7 and increases TGFB1 and GIMAP7 expression in T cells in subjects with COVID-19

Nasal anti-CD3 mAb (Foralumab) dampens CD3+ T effector function and decreases NKG7 in COVID-19 through a mechanism involving GIMAP-7 and TGFb1

Investigation and verification of GAMAP6 as a robust biomarker for prognosis and tumor immunity in lung adenocarcinoma

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