Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis

Xie, Jianmin; Zitao, Wang; Wang, Wen

doi:10.3389/fimmu.2020.02151

Cited by 33 publications

(31 citation statements)

References 46 publications

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“…SEMA4D regulates cell proliferation by interacting with CD72 [ 43 , 44 ]. It downregulates the differentiation of regulatory T (Treg) cells by inhibiting Foxp3 expression [ 45 ]. In addition, antibody blockade of SEMA4D increases the efficiency of anti-PD1 and anti-CTLA4 immunotherapies [ 46 , 47 ].…”

Section: Resultsmentioning

confidence: 99%

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

Biswas

Guemiri

Cadix

et al. 2022

Cancers

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Targeting the translation initiation complex eIF4F, which binds the 5′ cap of mRNAs, is a promising anti-cancer approach. Silvestrol, a small molecule inhibitor of eIF4A, the RNA helicase component of eIF4F, inhibits the translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor, which, in turn, reduces the transcription of the gene encoding one of the major immune checkpoint proteins, i.e., programmed death ligand-1 (PD-L1) in melanoma cells. A large proportion of human genes produce multiple mRNAs differing in their 3′-ends through the use of alternative polyadenylation (APA) sites, which, when located in alternative last exons, can generate protein isoforms, as in the STAT1 gene. Here, we provide evidence that the STAT1α, but not STAT1β protein isoform generated by APA, is required for silvestrol-dependent inhibition of PD-L1 expression in interferon-γ-treated melanoma cells. Using polysome profiling in activated T cells we find that, beyond STAT1, eIF4A inhibition downregulates the translation of some important immune-related mRNAs, such as the ones encoding TIM-3, LAG-3, IDO1, CD27 or CD137, but with little effect on the ones for BTLA and ADAR-1 and no effect on the ones encoding CTLA-4, PD-1 and CD40-L. We next apply RT-qPCR and 3′-seq (RNA-seq focused on mRNA 3′ ends) on polysomal RNAs to analyze in a high throughput manner the effect of eIF4A inhibition on the translation of APA isoforms. We identify about 150 genes, including TIM-3, LAG-3, AHNAK and SEMA4D, for which silvestrol differentially inhibits the translation of APA isoforms in T cells. It is therefore crucial to consider 3′-end mRNA heterogeneity in the understanding of the anti-tumor activities of eIF4A inhibitors.

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Section: Resultsmentioning

confidence: 99%

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

Biswas

Guemiri

Cadix

et al. 2022

Cancers

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“…The inhibitory effect of the external Sema4D on Treg cells in vitro was reported recently by Xie and associates [41]. This study used PBMC isolated from blood samples of normal control donors and of patients with ankylosing spondylitis.…”

Section: Discussionmentioning

confidence: 88%

Identifying Function Determining Residues in Neuroimmune Semaphorin 4A

Chapoval

Lee

Lemmer

et al. 2022

IJMS

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Semaphorin 4A (Sema4A) exerts a stabilizing effect on human Treg cells in PBMC and CD4+ T cell cultures by engaging Plexin B1. Sema4A deficient mice display enhanced allergic airway inflammation accompanied by fewer Treg cells, while Sema4D deficient mice displayed reduced inflammation and increased Treg cell numbers even though both Sema4 subfamily members engage Plexin B1. The main objectives of this study were: 1. To compare the in vitro effects of Sema4A and Sema4D proteins on human Treg cells; and 2. To identify function-determining residues in Sema4A critical for binding to Plexin B1 based on Sema4D homology modeling. We report here that Sema4A and Sema4D display opposite effects on human Treg cells in in vitro PBMC cultures; Sema4D inhibited the CD4+CD25+Foxp3+ cell numbers and CD25/Foxp3 expression. Sema4A and Sema4D competitively bind to Plexin B1 in vitro and hence may be doing so in vivo as well. Bayesian Partitioning with Pattern Selection (BPPS) partitioned 4505 Sema domains from diverse organisms into subgroups based on distinguishing sequence patterns that are likely responsible for functional differences. BPPS groups Sema3 and Sema4 into one family and further separates Sema4A and Sema4D into distinct subfamilies. Residues distinctive of the Sema3,4 family and of Sema4A (and by homology of Sema4D) tend to cluster around the Plexin B1 binding site. This suggests that the residues both common to and distinctive of Sema4A and Sema4D may mediate binding to Plexin B1, with subfamily residues mediating functional specificity. We mutated the Sema4A-specific residues M198 and F223 to alanine; notably, F223 in Sema4A corresponds to alanine in Sema4D. Mutant proteins were assayed for Plexin B1-binding and Treg stimulation activities. The F223A mutant was unable to stimulate Treg stability in in vitro PBMC cultures despite binding Plexin B1 with an affinity similar to the WT protein. This research is a first step in generating potent mutant Sema4A molecules with stimulatory function for Treg cells with a view to designing immunotherapeutics for asthma.

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“…However, the function of Sema4D on Treg responses in cancer is still unknown. In ankylosing spondylitis, Sema4D inhibits Treg cell differentiation in the AhR pathway (77). Sema4D also promotes liver fibrosis in Schistosomiasis infection via TGF-b1 and IL-13 pathways.…”

Section: Sema4dmentioning

confidence: 99%

Semaphorins as Potential Immune Therapeutic Targets for Cancer

et al. 2022

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Semaphorins are a large class of secreted or membrane-bound molecules. It has been reported that semaphorins play important roles in regulating several hallmarks of cancer, including angiogenesis, metastasis, and immune evasion. Semaphorins and their receptors are widely expressed on tumor cells and immune cells. However, the biological role of semaphorins in tumor immune microenvironment is intricate. The dysregulation of semaphorins influences the recruitment and infiltration of immune cells, leading to abnormal anti-tumor effect. Although the underlying mechanisms of semaphorins on regulating tumor-infiltrating immune cell activation and functions are not fully understood, semaphorins can notably be promising immunotherapy targets for cancer.

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Semaphorin 4D Induces an Imbalance of Th17/Treg Cells by Activating the Aryl Hydrocarbon Receptor in Ankylosing Spondylitis

Cited by 33 publications

References 46 publications

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

Identifying Function Determining Residues in Neuroimmune Semaphorin 4A

Semaphorins as Potential Immune Therapeutic Targets for Cancer

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