CD96 expression determines the inflammatory potential of IL-9–producing Th9 cells

Stanko, Katarina; Iwert, Christina; Appelt, Christine; Vogt, Katrin; Schümann, Julia; Strunk, Franziska Janina; Ahrlich, Stefanie; Schlickeiser, Stephan; Romagnani, Chiara; Jürchott, Karsten; Meisel, Christian; Willimsky, Gerald; Kühl, Anja A.; Sawitzki, Birgit

doi:10.1073/pnas.1708329115

Cited by 36 publications

(35 citation statements)

References 48 publications

(64 reference statements)

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“…Tissue distribution and activation of TH9 cells will determine their impact. So far, TH9 cells are preferentially found in the skin and are recruited to mucosal surfaces (Clark & Schlapbach, ; Stanko et al, ). IL9 receptor‐expressing cells include T cells, mainly of the CD4 subtype, hematopoietic precursor cells, mast cells, epithelial cells, and airway smooth muscle cells (Kaplan et al, ).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment.

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Section: Discussionmentioning

confidence: 99%

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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“…Although initially described as an activating receptor that stimulates NK cell cytotoxicity, 49 more recent data suggest that it has a predominant inhibitory function in both NK cells and T cell subsets. 40,50 The discrepancy in these findings might be due to pronounced differences in CD96 between species. 47,85 Nevertheless, CD96 has many similarities to TIGIT, indicating that it has an inhibitory role.…”

Section: Rationale For the Development Of Strategies Targeting Pvr Inmentioning

confidence: 94%

“…46 Finally, PVR also binds to CD96, another receptor member of the immunoglobulin superfamily that was initially inconsistently characterized in different species using various assays, [47][48][49] but has recently been described as an inhibitory receptor on Th9 and NK cells. 40,50 In other words, PVR functions as an immunoregulatory molecule that impacts the outcome of the immune response by interacting with activating and inhibitory receptors.…”

Section: Introductionmentioning

confidence: 99%

Targeting PVR (CD155) and its receptors in anti-tumor therapy

Brlić

Roviš

Cinamon³

et al. 2018

Cell Mol Immunol

115

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Poliovirus receptor (PVR, CD155) has recently been gaining scientific interest as a therapeutic target in the field of tumor immunology due to its prominent endogenous and immune functions. In contrast to healthy tissues, PVR is expressed at high levels in several human malignancies and seems to have protumorigenic and therapeutically attractive properties that are currently being investigated in the field of recombinant oncolytic virotherapy. More intriguingly, PVR participates in a considerable number of immunoregulatory functions through its interactions with activating and inhibitory immune cell receptors. These functions are often modified in the tumor microenvironment, contributing to tumor immunosuppression. Indeed, increasing evidence supports the rationale for developing strategies targeting these interactions, either in terms of checkpoint therapy (i.e., targeting inhibitory receptors) or in adoptive cell therapy, which targets PVR as a tumor marker.

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“…Moreover, researchers found higher intratumoral CD96 expression of human hepatocellular carcinoma exhibit poorer clinical outcomes 14 . Another group found that CD96 controls cytokine and colitis-inducing potential of Th9 cells, indicating blockade of CD96-mediated immune inhibition would be a promising approach in reinforcement of Th9-mediated immune control of tumors 15 . Therefore, CD96 shows potential as a new checkpoint target to uncover drugs that could complement existing immune checkpoint blockade therapies.…”

mentioning

confidence: 99%

CD96, a new immune checkpoint, correlates with immune profile and clinical outcome of glioma

Liu

Huang

et al. 2020

Sci Rep

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CD96 is a promising candidate for immunotherapy. However, its role and importance in glioma remains unknown. We thus aimed to genetically and clinically characterize CD96 expression in gliomas. For this, we extracted RNA-seq data of 699 glioma samples from the TCGA dataset and validated these findings using the CGGA dataset comprising 325 glioma samples. Clinical and isocitrate dehydrogenase (IDH) mutation status were also analyzed. Various packages in R language were mainly used for statistical analysis. CD96 expression was significantly up-regulated in high-grade, IDH-wildtype, and mesenchymal-molecular subtype gliomas based on TCGA data, which was validated using the CGGA dataset. Subsequent gene ontology analysis of both datasets suggested that genes relevant to CD96 are mainly involved in immune functions in glioma as such genes were positively correlated with CD96 expression. To further explore the relationship between CD96 and immune responses, we selected seven immune-related metagenes and found that CD96 expression was positively correlated with HCK, LCK, and MHC II in the CGGA and TCGA cohorts but negatively associated with IgG. Further, Pearson correlation analysis showed that CD96 is associated with TIGIT, CD226, CRTAM, TIM-3, PD-L1, CTLA-4, and STAT3, indicating the additive antitumoral effects of these checkpoint proteins. CD96 was also suggested to play an important role in immune responses and positively collaborate with other checkpoint members. These findings show that CD96 is promising candidate for immunotherapy, and that such agents could complement current immunotherapy strategies for glioma.

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CD96 expression determines the inflammatory potential of IL-9–producing Th9 cells

Cited by 36 publications

References 48 publications

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Targeting PVR (CD155) and its receptors in anti-tumor therapy

CD96, a new immune checkpoint, correlates with immune profile and clinical outcome of glioma

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