Sustained exposure to bacterial antigen induces interferon-γ-dependent T cell receptor ζ down-regulation and impaired T cell function

Bronstein-Sitton, Noemı́; Cohen-Daniel, Leonor; Vaknin, Ilan; Ezernitchi, Analía V.; Leshem, B.; Halabi, Amal; Houri-Hadad, Y; Greenbaum, Eugenia; Zakay‐Rones, Zichria; Shapira, Lior; Baniyash, Michal

doi:10.1038/ni975

Cited by 127 publications

(127 citation statements)

References 41 publications

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“…5A). Recent evidence shows that the generally impaired T cell function in chronic inflammation results from down-regulation of the CD3 chain in vivo (while other TCR complex subunits remain preserved), thus reflecting the impact of this adaptor molecule on T cell functionality (13). As CD3 is the main signaling adaptor molecule for NKp30 and NKp46 cytotoxicity receptors (17), the relative deficiency in this molecule in CD56 bright CD16 Ϫ FIGURE 2.…”

Section: Cd56 Bright Cd16 ϫ Vs Cd56 Dim Cd16 ϩ Nk Cells: Molecules Inmentioning

confidence: 99%

Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling

Hanna¹,

Bechtel

Zhai

et al. 2004

The Journal of Immunology

143

147

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As part of the innate immune system, human NK cells play a critical role early in the systemic host defense against pathogens and tumor cells. Recent studies suggest a more complex view of NK cell behavior, as different functions and tissue localizing capabilities seem to be preferentially assigned to distinct subpopulations of NK cells, CD56dimCD16+ or CD56brightCD16−. In this study, we used oligonucleotide microarrays to compare the expression profile of ∼20,000 genes in three NK cell subpopulations: peripheral blood-derived CD56dimCD16+, CD56brightCD16−, and in vitro-activated CD16+ NK cells. The differential expression of selected genes was verified by flow cytometry and functional assays. When comparing CD56dimCD16+ and CD56brightCD16− subsets, a new heterogeneous molecular basis for the functional and developmental differences between these two subsets was revealed. Furthermore, systematic analysis of transcriptional changes in activated CD16+ NK cells provided us with a better understanding of NK function in inflamed tissues. We highlight a number of genes that were overexpressed upon activation (e.g., OX40 ligand, CD86, Tim3, galectins, etc.), that enable these cells to directly cross-talk with other innate and adaptive immune effectors. The overexpressed genes assign novel intriguing immunomodulatory functions to activated NK cells, in addition to their potent cytotoxic abilities.

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Section: Cd56 Bright Cd16 ϫ Vs Cd56 Dim Cd16 ϩ Nk Cells: Molecules Inmentioning

confidence: 99%

Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling

Hanna¹,

Bechtel

Zhai

et al. 2004

The Journal of Immunology

143

147

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“…It has been well documented that various cytokines, chemokines, and growth factors including IL-1β, IL-6, IL-10, Ccl2 (MCP-1), Ccl3 (MIP-1α), GM-CSF, VEGF, and TGF-β are needed to drive MDSC migration into tumor lesions and to keep their suppressive phenotype in tumor-bearing hosts (6,9,(11)(12)(13)35). We also detected an accumulation of IFN-γ in melanoma lesions, which is known to be released by activated T cells, leading to the MDSC recruitment into the chronic inflammatory area and to the stimulation of NO production by these cells (6,9,11,14,36).…”

Section: Discussionmentioning

confidence: 75%

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model

Meyer

Sevko

Ramacher

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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310

255

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Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1 + CD11b + myeloidderived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.therapy | cytokines

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“…Certainly, an acute raise in extracellular urate levels due to any tissue damage may enhance T-cell immune response both indirectly by activating APCs (1-3,8), and according to this and other studies directly (9)(10)(11). Nevertheless, in the chronic hyperuricemic state, the opposite may occur since chronic inflammation (30,(35)(36)(37), or TCR-complex activation (17,18), resulting in ζ-chain downregulation.…”

Section: Discussionmentioning

confidence: 95%

Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation

et al. 2017

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Abstract. Uric acid is a known danger associated molecular pattern molecule able to induce inflammation following internalization of its crystals by cells of the innate immune system. By activating antigen-presenting cells, urate boosts adaptive immunity as well. Furthermore, urate crystals can induce proliferation of isolated T-cells, which are unable to phagocytose crystal particles. In light of the evidence that urate crystals can also activate dendritic cells and macrophages without prior internalization but through sequestration of lipid rafts (and consequently receptors clustering in a non specific manner), the authors evaluated whether such a mechanism is involved in the direct activation of T-cells by urate crystals. In the present study, isolated human T-cells were cultured with or without urate at a concentration above its crystallization level. The expression and phosphorylation state of the T-cell receptor (TCR) complex zeta chain and the expression of the master regulator of cell proliferation c-Myc were assessed by western blotting. T-cell proliferation was measured by bromodeoxyuridine assay. Collectively, the results indicated that urate increased zeta chain phosphorylation indicating that it induces activation of TCR complex directly, since zeta chain phosphorylation takes place at the cell membrane and is a very proximal event in TCR complex-mediated signal transduction. In parallel, urate increased the expression of the transcription factor c-Myc and induced T-cell proliferation. In conclusion, urate crystals directly activate the TCR complex and induce T-cell proliferation.

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Sustained exposure to bacterial antigen induces interferon-γ-dependent T cell receptor ζ down-regulation and impaired T cell function

Cited by 127 publications

References 41 publications

Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling

Novel Insights on Human NK Cells’ Immunological Modalities Revealed by Gene Expression Profiling

Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model

Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation

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