Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling

Okoye, Isobel; Namdar, Afshin; Xu, Lai; Crux, Nicole B.; Elahi, Shokrollah

doi:10.18632/oncotarget.21003

Cited by 31 publications

(31 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, we measured the proliferative capacity of CD8 + T cells restricted by different HLA-alleles using CFSE assay according to our previous reports[ 23 , 27 ]. We observed that epitope-specific CD8 + T cells restricted by HLA-B*35Px/B*53 had substantially lower proliferation capacity compared to CD8 + T cells restricted by HLA-B*27/B*57 alleles ( Fig 2F and 2G ).…”

Section: Resultsmentioning

confidence: 99%

“…Upon exposure to their cognate epitopes, CD8 + T cells upregulate the expression of co-inhibitory receptors, such as PD-1, TIM-3, and CTLA-4 to self-limit their activation [ 3 , 22 , 23 ]. However, chronic upregulation of co-inhibitory receptors and engagement with their corresponding ligands on antigen-presenting cells (APCs) or Tregs results in the impairment of CTLs functions [ 22 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…Exhausted CD8 + T cells exhibit impaired effector functions such as cytokine production, proliferate capacity, and cytotoxicity. Instead, they manifest sustained upregulation and co-expression of multiple co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3, and other co-inhibitory receptors[ 22 , 23 ]. However, the dysfunctionality of antigen-specific CTLs restricted by HLA-B*35Px in terms of these immune checkpoints has never been well studied before.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

2020

Self Cite

View full text Add to dashboard Cite

HLA-B*35Px is associated with HIV-1 disease rapid progression to AIDS. However, the mechanism(s) underlying this deleterious effect of this HLA allele on HIV-1 infection outcome has not fully understood. CD8 + T cells play a crucial role to control the viral replication but impaired CD8 + T cells represent a major hallmark of HIV-1 infection. Here, we examined the effector functions of CD8 + T cells restricted by HLA-B*35Px (HLA-B*35:03 and HLA-B*35:02), HLA-B*27/B57 and non-HLA-B*27/B57 (e.g. HLA-A*01, A*02, A*03, A*11, A*24, A*26, B*40, B*08, B*38, B*44). CD8 + T cells restricted by HLA-B*35Px exhibited an impaired phenotype compared with those restricted by HLA-B*27/B57 and even non-HLA-B*27/B57. CD8 + T cells restricted by non-HLA-B*27/B57 when encountered their cognate epitopes upregulated TIM-3 and thus became suppressed by regulatory T cells (Tregs) via TIM-3: Galectin-9 (Gal-9). Strikingly, CD8 + T cells restricted by HLA-B*35Px expressed fewer TIM-3 and therefore did not get suppressed by Tregs, which was similar to CD8 + T cells restricted by HLA-B*27/B57. Instead, CD8 + T cells restricted by HLA-B*35Px upon recognition of their cognate epitopes upregulated CTLA-4. The transcriptional and impaired phenotype (e.g. poor effector functions) of HIV-specific CD8 + T cells restricted by HLA-B*35 was related to persistent CTLA-4, elevated Eomes and blimp-1 but poor T-bet expression. As such, anti-CTLA-4 antibody, Ipilimumab, reversed the impaired proliferative capacity of antigen-specific CD8 + T cells restricted by HLA-B*35Px but not others. This study supports the concept that CD8 + T resistance to Tregs-mediated suppression is related to allele restriction rather than the epitope specificity. Our results aid to explain a novel mechanism for the inability of HIV-specific CD8 + T cells restricted by HLA-B*35Px to control viral replication.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…5F). In parallel we examined whether atorvastatin, due to its immunomodulatory properties as we previously reported 38,49 , can modulate ACE2 expression. However, this was not the case (Extended Data Fig.…”

Section: Cecs Get Infected With Sars-cov-2 and Dexamethasone Reduces mentioning

confidence: 96%

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Shahbaz

Sligl

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

SARS-CoV-2 infection is associated with lower blood oxygen levels even in patients without hypoxia requiring hospitalization. This discordance illustrates the need for a more unifying explanation as to whether SARS-CoV-2 directly or indirectly affects erythropoiesis. Here we show significantly enriched CD71+ erythroid precursors/progenitors in the blood circulation of COVID-19 patients that have distinctive immunosuppressive properties. A subpopulation of abundant erythroid cells, CD45+CD71+cells, co-express ACE2, TMPRSS2, CD147, CD26 and these can be infected with SARS-CoV-2. In turn, pre-treatment of erythroid cells with dexamethasone significantly diminished ACE2/TMPRSS2 expression and subsequently reduced their infectivity with SARS-CoV-2. Taken together, pathological abundance of erythroid cells might reflect stress erythropoiesis due to the invasion of erythroid progenitors by SARS-CoV-2. This may provide a novel insight into the impact of SARS-CoV-2 on erythropoiesis and hypoxia seen in COVID-19 patients.

show abstract

“…This is reflected by a trend in higher expression of inhibitory receptors on CD4 + T cells in C-section delivered cord blood. Inhibitory receptors can be considered as activation markers in an acute setting but in chronic conditions these receptors are associated with T cell exhaustion[ 22 , 23 ]. Furthermore, we analyzed the expression of some genes [TGF-β, NOX2, arginase-2, V-domain Ig suppressor of T cell activation (VISTA) and VEGFα] associated with immunological properties of CD71 + erythroid cells as we have described elsewhere[ 13 , 14 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

Mode of delivery by an ulcerative colitis mother in a case of twins: Immunological differences in cord blood and placenta

Dunsmore¹,

Koleva²,

Sutton³

et al. 2018

WJG

Self Cite

View full text Add to dashboard Cite

AIMTo understand the effects of delivery mode on the immune cells frequency and function in cord blood and placenta.METHODSWe evaluated immunological differences in cord blood and placental tissues for a case of twins one of which delivered vaginally while the other delivered by caesarian section (C-section). Cord blood mononuclear cells were isolated and placenta tissues were processed for cell isolation. Immune phenotyping was performed by flow cytometry methods following staining for T cells, natural killer (NK) cells, monocytes, neutrophils and CD71+ erythroid cells in both cord blood and placenta tissues. In addition, fetal calprotectin of twins was measured 12 wk after birth.RESULTSWe found lower percentages of immune cells (e.g. T cells, monocytes and neutrophils) in the cord blood of C-section delivered compared to vaginally delivered newborn. In contrast, percentages of monocytes and neutrophils were > 2 folds higher in the placental tissues of C-section delivered newborn. More importantly, we observed lower percentages of CD71+ erythroid cells in both cord blood and placental tissues of C-section delivered case. Lower CD71+ erythroid cells were associated with a more pro-inflammatory milieu at the fetomaternal interface reflected by higher expression of inhibitory receptors on CD4+ T cells, higher frequency of monocytes and neutrophils. Furthermore, type of delivery impacted the gene expression profile in CD71+ erythroid cells. Finally, we found that C-section delivered child had > 20-fold higher FCP in his fecal sample at 12 wk of age.CONCLUSIONMode of delivery impacted immune cells profile in cord blood/placenta. In particular frequency of immunosuppressive CD71+ erythroid cells was reduced in C-section delivered newborn.

show abstract

Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling

Cited by 31 publications

References 84 publications

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection

Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Mode of delivery by an ulcerative colitis mother in a case of twins: Immunological differences in cord blood and placenta

Contact Info

Product

Resources

About