High Levels of Eomes Promote Exhaustion of Anti-tumor CD8+ T Cells

Li, Jing; He, Yi; Hao, Jun; Ni, Ling; Dong, Chen

doi:10.3389/fimmu.2018.02981

Cited by 151 publications

(147 citation statements)

References 36 publications

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“…This increase in PD-1 and EOMES expression was accompanied by a reduction in IFNγ production, suggesting that IL-10R signaling is additionally involved in the regulation of the effector activity of CD4 + T-cells. This is in line with published results for CD8 + T-cells, showing that overexpression of EOMES resulted in an increased expression of exhaustion molecules such as CD244, Havcr2 as well as Il10ra , implicating a role for IL-10-mediated signaling in regulating T-cell exhaustion (54). Moreover, during murine chronic viral infections, CD4 + T-cells upregulate EOMES as well as inhibitory receptors that are associated with T-cell exhaustion (43).…”

Section: Discussionsupporting

confidence: 92%

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

Roessner

Lupar

et al. 2020

Preprint

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41The transcription factor Eomesodermin (EOMES) promotes IL-10 production of CD4 + T-cells, which has 42 been linked to immunosuppressive and cytotoxic activities. We detected EOMES-expressing CD4 + T-43 cells in lymph node samples of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell 44 lymphoma. This was in line with an observed expansion of EOMES-positive CD4 + T-cells in leukemic Eµ-45 TCL1 mice, a well-established model of CLL, and upon adoptive transfer of TCL1 leukemia in mice. 46Transcriptome and flow cytometry analyses revealed that EOMES does not only drive the transcription 47 of IL-10, but rather controls a unique differentiation program in CD4 + T-cells. Moreover, EOMES was 48 necessary for the accumulation of a specific CD4 + T-cell subset that expresses IFNγ and IL-10, as well 49 as inhibitory receptors, like PD-1 and LAG3. T-cell transfer studies in leukopenic Rag2 -/mice showed 50 that EOMES-deficient CD4 + T-cells were inferior in controlling TCL1 leukemia development compared 51 to wildtype T-cells, even though expansion of Eomes -/-CD4 + T-cells was observed. We further showed 52 that control of TCL1 leukemia was driven by IL-10 receptor-mediated signals, as Il10rb-deficient CD4 + 53 T-cells showed impaired anti-leukemia activity. Altogether, our data suggest that IL-10 producing PD-54

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Section: Discussionsupporting

confidence: 92%

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

Roessner

Lupar

et al. 2020

Preprint

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“…In summary, we show here that despite the strong and uniform induction of Eomes in CD8 T cells from Tbx21 E/E mice, we did not observe a rescue of the Tbx21 -/phenotype in the context of LCMV infection with respect to clonal expansion, effector differentiation and responsiveness towards cytokines or chemokines. This would be in line with a model, in which there is a only limited functional overlap in the transcriptional activity of T-bet and Eomes [34].…”

Section: Plos Pathogenssupporting

confidence: 85%

Eomes cannot replace its paralog T-bet during expansion and differentiation of CD8 effector T cells

et al. 2020

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The two T-box transcription factors T-bet and Eomesodermin (Eomes) are important regulators of cytotoxic lymphocytes (CTLs), such as activated CD8 T cells, which are essential in the fight against intracellular pathogens and tumors. Both transcription factors share a great degree of homology based on sequence analysis and as a result exert partial functional redundancy during viral infection. However, the actual degree of redundancy between T-bet and Eomes remains a matter of debate and is further confounded by their distinct spatiotemporal expression pattern in activated CD8 T cells. To directly investigate the functional overlap of these transcription factors, we generated a new mouse model in which Eomes expression is under the transcriptional control of the endogenous Tbx21 (encoding for Tbet) locus. Applying this model, we demonstrate that the induction of Eomes in lieu of T-bet cannot rescue T-bet deficiency in CD8 T cells during acute lymphocytic choriomeningitis virus (LCMV) infection. We found that the expression of Eomes instead of T-bet was not sufficient for early cell expansion or effector cell differentiation. Finally, we show that imposed expression of Eomes after acute viral infection promotes some features of exhaustion but must act in concert with other factors during chronic viral infection to establish all hallmarks of exhaustion. In summary, our results clearly underline the importance of T-bet in guiding canonical CTL development during acute viral infections.

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“…As for EOMES and T-bet, they are linked with cell exhaustion and chronic infection. EOMES can cause exhaustion in tumor-infiltrating cells (Li et al, 2018), and chronic infection with HIV is linked to increased T-bet and EOMES expression (Buggert et al, 2014). It appears that the expression of EOMES and T-bet in T cells from patients with SLE (F and G) Degranulation (%CD107a) of CD8CD38 low or CD8CD38 high T cells from healthy subjects (F) and from patients with SLE (G) treated with GSK126 overnight and stimulated with plate-coated CD3/CD28 antibodies for 5 h with GSK126 at the indicated concentration (n = 4, one-way ANOVA with multiple comparisons).…”

Section: Discussionmentioning

confidence: 99%

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

et al. 2020

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Graphical Abstract Highlights d Expanded CD8CD38 high T cells in SLE patients identify patients with infections d CD8CD38 high T cells express decreased amounts of cytotoxic molecules d CD38 decreases NAD + and SIRT1 activity and releases the activity of EZH2 d Inhibition of EZH2 restores the degranulation capacity of CD8CD38 high T cells In Brief Katsuyama et al. find that an expanded CD8CD38 high T cell population in SLE patients is linked to infections. CD8CD38 high T cells display decreased cytotoxic capacity by suppressing the expression of related molecules through an NAD + /Sirtuin1/EZH2 pathway. EZH2 inhibitors increase cytotoxicity offering a means to mitigate infection rates in SLE. SUMMARYPatients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38 high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38 high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38 high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

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High Levels of Eomes Promote Exhaustion of Anti-tumor CD8+ T Cells

Cited by 151 publications

References 36 publications

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

Eomes cannot replace its paralog T-bet during expansion and differentiation of CD8 effector T cells

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

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High Levels of Eomes Promote Exhaustion of Anti-tumor CD8+ T Cells

Cited by 151 publications

References 36 publications

EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

EOMES and IL-10 regulate anti-tumor activity of PD-1+CD4+T-cells in B-cell Non-Hodgkin lymphoma

Eomes cannot replace its paralog T-bet during expansion and differentiation of CD8 effector T cells

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections

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EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma

EOMES and IL-10 regulate anti-tumor activity of PD-1⁺CD4⁺T-cells in B-cell Non-Hodgkin lymphoma