TNFR2 Expression on CD25hiFOXP3+ T Cells Induced upon TCR Stimulation of CD4 T Cells Identifies Maximal Cytokine-Producing Effectors

Govindaraj, Chindu; Scalzo-Inguanti, Karen; Scholzen, Anja; Li, Shuo; Plebanski, Magdalena

doi:10.3389/fimmu.2013.00233

Cited by 26 publications

(25 citation statements)

References 26 publications

(36 reference statements)

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“…It is important to note that our data do not demonstrate a proliferative advantage in TNFR2 hi cells, as a similar proportion of TNFR2 hi and TNFR2 lo cells were BrDU + in both high and low affinity primed groups. This is in line with a previous study that found no difference in proliferation between human CD4 + T cells with high or intermediate levels of TNFR2 expression (11, 13). While we have established a functional role for blocking TNFR2 signals in the context of transplantation, we cannot determine whether this is a CD8 + T cell intrinsic effect or if other cell types are playing a role in these observations.…”

Section: Discussionsupporting

confidence: 93%

Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity

Krummey

Chen

Guasch

et al. 2016

The Journal of Immunology

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The affinity of a T cell receptor (TCR) binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic antigen and mediate graft rejection. We found that low affinity primed memory CD8+ T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared to high affinity primed memory T cells. Low affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2hi proliferating cells. Low affinity primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low but not high affinity primed animals. These data establish a functional connection between TNF signaling and TCR priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation.

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Section: Discussionsupporting

confidence: 93%

Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity

Krummey

Chen

Guasch

et al. 2016

The Journal of Immunology

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“…Moreover, only increases TNFR2 + Tregs (Figure 4 B), but not TNFR2 − Tregs (Figure 4 C) were inversely correlated with effector CD4 T cell function. Given we found ascites also increased TNFR2 + Teffs, and these cells are reported as hyperactive cytokine producers ( 77 ), we tested whether conventional Tregs would be able to suppress their cytokine production. Figure 4 D shows that there was no inverse relationship between conventional Tregs increases and TNFR2 + Teff IFN-γ production, showing they could not suppress this effector T cell subset.…”

Section: Resultsmentioning

confidence: 99%

“…Future studies could also address the influence of IL-6 on different subsets of TNFR2 expressing effector T cells. Previous studies have shown that TNFR2 + effectors were capable upon anti-CD3 and anti-CD28 stimulation of producing a range of cytokines including IFN-y, IL-2 and IL-10 ( 77 , 78 ). It would be particularly interesting to study the effect of IL-6 on cytokine producing Th17 cells given literature suggesting that Th17 plays an important role in the pathogenesis of diverse group of autoimmune diseases as well inflammatory diseases and cancers, including ovarian cancer ( 92 , 93 ).…”

Section: Discussionmentioning

confidence: 99%

Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells

et al. 2017

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BackgroundEpithelial ovarian cancer (EOC) remains a highly lethal gynecological malignancy. Ascites, an accumulation of peritoneal fluid present in one-third of patients at presentation, is linked to poor prognosis. High levels of regulatory T cells (Tregs) in ascites are correlated with tumor progression and reduced survival. Malignant ascites harbors high levels of Tregs expressing the tumor necrosis factor receptor 2 (TNFR2), as well as pro-inflammatory factors such as interleukin 6 (IL-6) and tumor necrosis factor (TNF). IL-6 is also associated with poor prognosis. Herein, we study the effect of IL-6 and TNF present in ascites on the modulation of TNFR2 expression on T cells, and specifically Tregs.MethodsAscites and respective peripheral blood sera were collected from 18 patients with advanced EOC and soluble biomarkers, including IL-6, sTNFR2, IL-10, TGF-β, and TNF, were quantified using multiplexed bead-based immunoassay. Peripheral blood mononuclear cells (PBMC) from healthy donors were incubated with cell-free ascites for 48 h (or media as a negative control). In some experiments, IL-6 or TNF within the ascites were neutralized by using monoclonal antibodies. The phenotype of TNFR2+ Tregs and TNFR2− Tregs were characterized post incubation in ascites. In some experiments, cell sorted Tregs were utilized instead of PBMC.ResultsHigh levels of immunosuppressive (sTNFR2, IL-10, and TGF-β) and pro-inflammatory cytokines (IL-6 and TNF) were present in malignant ascites. TNFR2 expression on all T cell subsets was higher in post culture in ascites and highest on CD4+CD25hiFoxP3+ Tregs, resulting in an increased TNFR2+ Treg/effector T cell ratio. Furthermore, TNFR2+ Tregs conditioned in ascites expressed higher levels of the functional immunosuppressive molecules programmed cell death ligand-1, CTLA-4, and GARP. Functionally, TNFR2+ Treg frequency was inversely correlated with interferon-gamma (IFN-γ) production by effector T cells, and was uniquely able to suppress TNFR2+ T effectors. Blockade of IL-6, but not TNF, within ascites decreased TNFR2+ Treg frequency. Results indicating malignant ascites promotes TNFR2 expression, and increased suppressive Treg activity using PBMC were confirmed using purified Treg subsets.ConclusionIL-6 present in malignant ovarian cancer ascites promotes increased TNFR2 expression and frequency of highly suppressive Tregs.

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“…Pharmacologic interventions designed to selectively target ADO and PGE2 pathways could not only inhibit the tumor-derived factors but also silence the suppressive activities of Tregs and thus restore the anti-tumor activity of T effector cells. The last research article shows that a subpopulation of CD25hiTNFR2+ cells generated in vitro from CD4+ cells through TCR stimulation express FOXP3 and other Treg markers, but have effector functions rather than suppressive characteristics ( 21 ).…”

mentioning

confidence: 99%

Thymus-Derived, Peripherally Derived, and in vitro-Induced T Regulatory Cells

Elkord

2014

Front. Immunol.

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TNFR2 Expression on CD25hiFOXP3+ T Cells Induced upon TCR Stimulation of CD4 T Cells Identifies Maximal Cytokine-Producing Effectors

Cited by 26 publications

References 26 publications

Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity

Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low-Affinity Memory CD8+ T Cells during Heterologous Immunity

Interleukin 6 Present in Inflammatory Ascites from Advanced Epithelial Ovarian Cancer Patients Promotes Tumor Necrosis Factor Receptor 2-Expressing Regulatory T Cells

Thymus-Derived, Peripherally Derived, and in vitro-Induced T Regulatory Cells

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