Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

Ventre, Erwan; Brinza, Lilia; Schicklin, Stéphane; Mafille, Julien; Coupet, Charles-Antoine; Marçais, Antoine; Djebali, Sophia; Jubin, V.; Walzer, Thierry; Marvel, Jacqueline

doi:10.4049/jimmunol.1102954

Cited by 27 publications

(41 citation statements)

References 50 publications

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“…This finding is similar to previous results showing that IL-4 downregulated NKG2D expression on human CD8 1 T and natural killer cells and suppressed anti-tumor immune responses. [49][50][51] In our previous study, we demonstrated that CD27 1 CD25 high Vd1 T cells have a regulatory function. 40 We plan to further compare the functions of NKG2D 2 Vd1 T cells and NKG2D 1 Vd1 T cells to examine whether the NKG2D 2 Vd1 T cells have regulatory effects.…”

Section: Il-4-induced Vd1 T-cell Bias Weakened the Overall Immune Resmentioning

confidence: 99%

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

et al. 2015

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Interleukin 4 (IL-4) has a variety of immune functions, including helper T-cell (Th-cell) differentiation and innate immune-response processes. However, the impact of IL-4 on gamma delta (cd) T cells remains unclear. In this study, we investigate the effects of IL-4 on the activation and proliferation of cd T cells and the balance between variable delta 1 (Vd1) and Vd2 T cells in humans. The results show that IL-4 inhibits the activation of cd T cells in the presence of cd T-cell receptor (TCR) stimulation in a STAT6-dependent manner. IL-4 promoted the growth of activated cd T cells and increased the levels of Vd1 T cells, which in turn inhibited Vd2 T-cell growth via significant IL-10 secretion. Vd1 T cells secreted significantly less interferon gamma (IFNc) and more IL-10 relative to Vd2. Furthermore, Vd1 T cells showed relatively low levels of Natural Killer Group 2D (NKG2D) expression in the presence of IL-4, suggesting that Vd1 T cells weaken the cd T cell-mediated anti-tumor immune response. For the first time, our findings demonstrate a negative regulatory role of IL-4 in cd T cell-mediated anti-tumor immunity. Cellular & Molecular Immunology

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Section: Il-4-induced Vd1 T-cell Bias Weakened the Overall Immune Resmentioning

confidence: 99%

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

et al. 2015

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“…1A). The Elk4 Elk1 –null innate-like αβ CD8 + SP thymocyte population expressed markers associated with conventional memory cells but not IL-4–induced memory-like cells, such as NKG2D, T-bet, and CCL5 (29) (Fig. 1D).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we have shown that ELK4 and ELK1 act redundantly and cell autonomously downstream of ERK signaling to limit the generation of innate-like αβ CD8 + T cells with memory characteristics in the thymus. These cells exhibit hallmarks of conventional memory CD8 + T cells, with enhanced expression of the T-box transcription factors Eomes and T-bet and increased proliferation and production of IFN-γ in response to TCR ligation (27–29). The effect of ELK4 inactivation is unlikely to reflect a change in TCR repertoire that preferentially selects innate-like cells because increased innate-like αβ CD8 + differentiation occurred in Elk4 -null cells expressing the MHC class I–specific F5 TCR.…”

Section: Discussionmentioning

confidence: 99%

ERK Signaling Controls Innate-like CD8+ T Cell Differentiation via the ELK4 (SAP-1) and ELK1 Transcription Factors

Maurice

Costello

Sargent

et al. 2018

The Journal of Immunology

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In mouse thymocyte development, signaling by the TCR through the ERK pathway is required for positive selection of conventional naive T cells. The Ets transcription factor ELK4 (SAP-1), an ERK-regulated cofactor of the SRF transcription factor, plays an important role in positive selection by activating immediate-early genes such as the Egr transcription factor family. The role of ELK4–SRF signaling in development of other T cell types dependent on ERK signaling has been unclear. In this article, we show that ELK4, and its close relative ELK1, act cell autonomously in the thymus to control the generation of innate-like αβ CD8+ T cells with memory-like characteristics. Mice lacking ELK4 and ELK1 develop increased numbers of innate-like αβ CD8+ T cells, which populate the periphery. These cells develop cell autonomously rather than through expansion of PLZF+ thymocytes and concomitantly increased IL-4 signaling. Their development is associated with reduced TCR-mediated activation of ELK4–SRF target genes and can be partially suppressed by overexpression of the ELK4–SRF target gene EGR2. Consistent with this, partial inhibition of ERK signaling in peripheral CD8+T cells promotes the generation of cells with innate-like characteristics. These data establish that low-level ERK signaling through ELK4 (and ELK1) promotes innate-like αβ CD8+ T cell differentiation, tuning conventional versus innate-like development.

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“…Several research groups have reported functional aspects of cytokines in which IL-2 [16,17], IL-15 [18,19] or the combination of IL-15 and TNF-α [20], have participated as key molecules, and observed a marked increased expression of the NKG2D receptor. In other studies, the dual functional role of cytokines has been demonstrated using IL-4 [21] or IL-21 [22], two well known inducers of NK cell maturation [23]. This last study suggested that both cytokines, the IL-4 and the IL-21, act as negative regulators of the NKG2D system in both NK and CD8+ T cells.…”

Section: Introductionmentioning

confidence: 88%

Cytokine Intervention: A Double Edged Sword in the Nkg2d System Regulation

Montalban-Arques¹

2014

Immunome Res

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The natural killer group 2 members D (NKG2D) is an activating receptor which plays a major role in immune surveillance, and the detection and elimination of malignant tumors and infected cells. NKG2D acts over both arms of the vertebrate immune response, and is expressed in some human and mouse myelopoietic, γδ T, NKT and CD4+ cells, but is present in all NK and CD8+ T cells in humans and activated mouse CD8+ T cells. In humans, eight ligands which selectively bind to the NKG2D receptor have been identified. These ligands are not systemically expressed, but are triggered in response to stress and expressed only under specific pathological states. Several research results point to the importance of cytokines for increasing expression of NKG2D to restore the functionality of NK cells as well as their ligands in the target cells. However, the NKG2D system itself in an activated state, also release pro and anti-inflammatory cytokine transcripts to establish communication with other cells or for self-regulation. Additionally, type I antiviral interferon is largely produced. Such cytokine interactions could be regarded as a double edged sword. This behavior is emphasized by a discrepancy regarding the functionality of cytokines which interact with, or on the NKG2D system. Indeed, they seem to protect the host and rather can induce ligand expression, cell proliferation or dissemination of malignant tumors, generating complicated cytokine-mediated messenger loops which are far from being fully understood. Whatever the case, cytokines related to the NKG2D system could be an attractive and useful target for immunotherapeutic approaches. Thus, here we briefly review recent findings on the main aspects involved in the regulation of this system and, particularly, attempt to clarify the role played by cytokines in the activating or inhibitory function they exert over the NKG2D system in different contexts.

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Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

Cited by 27 publications

References 50 publications

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

A new effect of IL-4 on human γδ T cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells

ERK Signaling Controls Innate-like CD8+ T Cell Differentiation via the ELK4 (SAP-1) and ELK1 Transcription Factors

Cytokine Intervention: A Double Edged Sword in the Nkg2d System Regulation

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