Characterization of the immunoregulatory function of human TCR‐αβ+ CD4−CD8− double‐negative T cells

Voelkl, Simon; Gary, Regina; Mackensen, Andréas

doi:10.1002/eji.201040982

Cited by 90 publications

(107 citation statements)

References 48 publications

(84 reference statements)

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“…We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4 + and CD8 + T cell responses (11). The suppressive activity of DN T cells is not mediated indirectly by modulation of APCs or by competition for T cell growth factors.…”

Section: Ouble-negative (Dn) T Cells Are Defined By the Expressionmentioning

confidence: 83%

“…In addition, other signaling pathways or transcription factors influenced by IL-7 appeared to be negligible for DN T cell functionality. Notably, we have previously demonstrated that IL-2 was not able to modulate suppressive activity of DN T cells, suggesting that IL-7 mediated Akt/mTOR signaling is highly significant in these cells (11). Several studies investigated the role of Akt/mTOR signaling in Treg cells.…”

Section: Discussionmentioning

confidence: 99%

“…Dendritic cells (DCs) were generated from leukapheresis products, as described previously (11). DN T cells (1 3 10 5 /well) were cocultured with allogeneic mature DCs (2.5 3 10 4 /well) in 96-well plates in complete medium plus IL-2.…”

Section: Isolation and Culture Of T Cellsmentioning

confidence: 99%

“…We demonstrated recently that human DN T cells restrain proliferation and activation of responder T cells (11). To confirm the impact of IL-7 on DN T cell-mediated suppression, we analyzed the expression of the activation markers CD154 and CD25 on CD4 + T cells (Fig.…”

Section: Il-7 Impairs Functionality Of Human Dn T Cellsmentioning

confidence: 99%

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IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Allgäuer

Schreiner

Ferrazzi

et al. 2015

The Journal of Immunology

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Recently, a novel subset of TCRαβ+ CD4− CD8− double-negative (DN) T cells was described to suppress immune responses in both mice and humans. Moreover, in murine models, infusion and/or activation of DN T cells specifically suppressed alloreactive T cells and prevented the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. We demonstrated that human DN T cells, like their murine counterparts, are highly potent suppressor cells of both CD4+ and CD8+ T cell responses. After hematopoietic stem cell transplantation and other lymphopenic conditions, IL-7 plays an important role in the reconstitution, survival, and homeostasis of the T cell compartment. Because IL-7 was shown to interfere with T cell functionality, we asked whether IL-7 affects the functionality of human DN T cells. Intriguingly, IL-7 diminished the suppressive activity of DN T cells toward allogeneic CD4+ effector T cells. Of interest, our studies revealed that IL-7 activates the Akt/mechanistic target of rapamycin (mTOR) pathway in human DN T cells. Importantly, selective inhibition of the protein kinases Akt or mTOR reversed the IL-7 effect, thereby restoring the functionality of DN T cells, whereas inhibition of other central T cell signaling pathways did not. Further analyses suggest that the IL-7/Akt/mTOR signaling cascade downregulates anergy-associated genes and upregulates activation- and proliferation-associated factors that may be crucial for DN T cell functionality. These findings indicate that IL-7 and Akt/mTOR signaling are critical factors for the suppressive capacity of DN T cells. Targeting of these pathways by pharmacological agents may restore and/or enhance DN T cell functionality in graft-versus-host disease.

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Section: Ouble-negative (Dn) T Cells Are Defined By the Expressionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Isolation and Culture Of T Cellsmentioning

confidence: 99%

Section: Il-7 Impairs Functionality Of Human Dn T Cellsmentioning

confidence: 99%

See 2 more Smart Citations

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Allgäuer

Schreiner

Ferrazzi

et al. 2015

The Journal of Immunology

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“…Another one third of the CD30 þ T cells included CD4/CD8 DN lymphocytes. DN T cells were recently shown to exert a regulatory/tolerogenic function (21,24,25) and to be enriched in the peripheral blood of melanoma patients (26). Functional studies performed with immunosorted CD30 þ lymphocytes from the nodes of stage III melanoma patients have demonstrated that these cells are endowed with low proliferative ability and a limited capacity to produce Th1 and Th2 cytokines.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

et al. 2014

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Sentinel lymph nodes set the stance of the immune system to a localized tumor and are often the first site to be colonized by neoplastic cells that metastasize. To investigate how the presence of neoplastic cells in sentinel lymph nodes may trigger pathways associated with metastatic progression, we analyzed the transcriptional profiles of archival sentinel node biopsy specimens obtained from melanoma patients. Biopsies from positive nodes were selected for comparable tumor infiltration, presence or absence of further regional node metastases, and relapse at 5-year follow-up. Unsupervised analysis of gene expression profiles revealed immune response to be a major gene ontogeny represented. Among genes upregulated in patients with progressing disease, the TNF receptor family member CD30/TNFRSF8 was confirmed in biopsy specimens from an independent group of patients. Immunohistochemical analysis revealed higher numbers of CD30 þ lymphocytes in nodes from progressing patients compared with nonprogressing patients. Phenotypic profiling demonstrated that CD30 þ lymphocytes comprised a broad population of suppressive or exhausted immune cells, such as CD4 þ Foxp3 þ or PD1 þ subpopulations and CD4 À CD8 À T cells. CD30 þ T lymphocytes were increased in peripheral blood lymphocytes of melanoma patients at advanced disease stages. Our findings reinforce the concept that sentinel nodes act as pivotal sites for determining progression patterns, revealing that the presence of CD30 þ lymphocytes at those sites associate positively with melanoma progression. Cancer Res; 74(1); 130-40. Ó2014 AACR.

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Profiling pharmacokinetics of double‐negative T cells and cytokines via a single intravenous administration in NSG mice

Xu¹,

Wang³

et al. 2021

Biopharm & Drug Disp

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This study was intended to delineate the profile of double-negative T cells (DNTs) in NOD.Cg-Prkdc scid Il2rg tm1wj /SzJ mice and cytokines released from DNTs in vivo and in vitro. Total 4 � 10 7 cells of RC1012 injection per mice were intravenously infused.IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-10 were measured in vivo and in vitro. A quantitative polymerase chain reaction (PCR) was employed to determine the gene copies of Notch2-NLA per DNT cell from collected organs. Cytokines were significantly increased in vitro (4 h) and in vivo (3 h). DNT cells were distributed into the lung, liver, heart, and kidney earlier, and redistributed to lymphocyte homing spleen and bone marrow, which seemed to frame a two-compartment pharmacokinetics (PK) model but more data are needed to confirm this, and the clearance of DNT cells fell into first-order kinetics.

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Characterization of the immunoregulatory function of human TCR‐αβ⁺ CD4⁻CD8⁻ double‐negative T cells

Cited by 90 publications

References 48 publications

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

IL-7 Abrogates the Immunosuppressive Function of Human Double-Negative T Cells by Activating Akt/mTOR Signaling

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

Profiling pharmacokinetics of double‐negative T cells and cytokines via a single intravenous administration in NSG mice

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