PI3Kδ inhibition modulates regulatory and effector T-cell differentiation and function in chronic lymphocytic leukemia

Hanna, Bola S.; Roessner, Philipp M.; Scheffold, Annika; Jebaraj, Billy Michael Chelliah; Demerdash, Yasmin; Öztürk, Selcen; Lichter, Peter; Stilgenbauer, Stephan; Seiffert, Martina

doi:10.1038/s41375-018-0318-3

Cited by 50 publications

(69 citation statements)

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“…Of note, the majority of these PD-1 + cells also expressed EOMES (Figure 2B) as well as the inhibitory receptor LAG3 (Supplementary Figure 2B). To overcome long latency of CLL development in this mouse model, leukemic splenocytes of TCL1 mice were retrieved and adoptively transfered into syngeneic WT mice (TCL1 AT), as previously described (6, 37, 40). Upon leukemia development in the TCL1 AT model, we observed an accumulation of antigen-experienced CD4 + T-cells (Supplementary Figure 2C) that show signs of activation as measured by CD69 (Supplementary Figure 2D).…”

Section: Resultsmentioning

confidence: 99%

“…In order to decipher the role of EOMES + PD-1 + CD4 + T-cells in CLL development, we transferred CD4 + T-cells into Rag2 -/- mice, which lack mature B- and T-cells (41). Subsequently, the mice were transplanted with TCL1 leukemia cells, as previously described (6, 37, 40). We detected an expansion of CD4 + T-cells in Rag2 -/- mice, which was similar with or without leukemia cell transfer (Supplementary Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…An altered frequency of CD4 + T-cell subsets in B-NHL patients is widely described (1, 3, 5, 6). Among these subsets, particularly IL-10-expressing Tregs were of interest during investigations, as they are thought to mediate immunosuppressive functions and thus contribute to disease progression (6).…”

Section: Discussionmentioning

confidence: 99%

“…Despite abundant data characterizing CD4 + T-cells and their subsets in B-cell Non-Hodgkin lymphoma (B-NHL) (1), and in particularly chronic lymphocytic leukemia (CLL) (2-6), their role in disease development and progression is poorly understood. Besides well-known T helper (Th) cell subsets (5), interleukin (IL-)10 producing, FOXP3 - conventional CD4 + T-cells, named type 1 regulatory (T R 1) cells, are gaining attention in mouse models as well as patients harboring chronic inflammatory conditions such as inflammatory bowel disease (7-10).…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…CD4 + T cells are a heterogenous population of cells, broadly divided into conventional (cCD4 + ) and regulatory (Treg) subsets. Previous studies showed Tregs to be enriched in CLL, although their depletion caused only limited changes in CLL progression in a mouse model of CLL (D'Arena et al, 2011;Hanna et al, 2019a).…”

Section: Introductionmentioning

confidence: 97%

TBET‐expressing Th1 CD4⁺T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice

et al. 2019

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Summary Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro‐ and anti‐tumour functions. In CLL, controversial reports describing the dominance of IFNγ‐expressing Th1 T cells or of IL‐4‐producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ‐TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21−/− bone marrow chimaeric mice which showed a lower number of IFNγ‐producing Th1 T cells, and used them for adoptive transfer of Eµ‐TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild‐type controls, excluding a major role for TBET‐expressing Th1 cells in Eµ‐TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.

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Ginkgo biloba extract promotes Treg differentiation to ameliorate ischemic stroke via inhibition of HIF‐1α/HK2 pathway

Hui,

Huang,

Zheng

et al. 2023

Phytotherapy Research

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The ischemic brain can dialogue with peripheral tissues through the immune system. Ginkgo biloba extract (EGb) was used to regulate various neurological disorders; however, the impact of EGb on ischemic stroke is still unclear. Here, we aimed to investigate whether immunomodulation has participated in the beneficial effects of EGb on ischemia/reperfusion (I/R) brain injury. Mice were orally administered with EGb once daily for 7 days before the induction of I/R. Neurobehavioral scores, infarct volume, and brain inflammation were determined. The proportion of CD4+ T cells was detected by flow cytometry. EGb significantly lowered neurobehavioral scores, infarct volume, and the level of inflammatory cytokines in I/R mice. Interestingly, EGb altered the proportion of CD4+ T cells, particularly increasing the proportion of Treg cells. Depletion of Treg cells weakened the neuroprotective effects of EGb on ischemic stroke; furthermore, EGb decreased the expression of HIF‐1α and HK2 and promoted the differentiation of Treg cells in vitro. EGb suppressed the HIF‐1α/HK2 signaling pathway to promote the differentiation of Treg cells and ameliorate ischemic stroke in mice. The expansion effect of EGb on Treg cells could be exploited as part of future stroke therapy.

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PI3Kδ inhibition modulates regulatory and effector T-cell differentiation and function in chronic lymphocytic leukemia

Cited by 50 publications

References 53 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

TBET‐expressing Th1 CD4⁺T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice

Ginkgo biloba extract promotes Treg differentiation to ameliorate ischemic stroke via inhibition of HIF‐1α/HK2 pathway

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PI3Kδ inhibition modulates regulatory and effector T-cell differentiation and function in chronic lymphocytic leukemia

Cited by 50 publications

References 53 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

TBET‐expressing Th1 CD4+T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice

Ginkgo biloba extract promotes Treg differentiation to ameliorate ischemic stroke via inhibition of HIF‐1α/HK2 pathway

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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

TBET‐expressing Th1 CD4⁺T cells accumulate in chronic lymphocytic leukaemia without affecting disease progression in Eµ‐TCL1 mice