Activated, But Not Resting, T Cells Can Be Recognized and Killed by Syngeneic NK Cells

Rabinovich, Brian A.; Li, Jennifer; Shannon, James A.; Hurren, Rose; Chalupny, Jan; Cosman, David; Miller, Richard G.

doi:10.4049/jimmunol.170.7.3572

Cited by 197 publications

(181 citation statements)

References 42 publications

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“…One hypothesis may be that induction of activated T cell apoptosis via NK-derived galectin-1 and 12 might act in concert with the described ability of syngeneic NK cells to recognize and kill activated, but not resting, CD4 ϩ and CD8 ϩ T cells. This would lead to attenuation of T cell activation and resolution of the immune response (60). Galectin 3 was another family member up-regulated in CD16 ϩ NK cells following activation (Figs.…”

Section: Activated Vs Unactivated Cd16 ϩ Nk Cells: Secreted Immune Efmentioning

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: Activated Vs Unactivated Cd16 ϩ Nk Cells: Secreted Immune Efmentioning

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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“…For example, NKG2D ligand expression was shown on activated T cells in both mouse and human, possibly representing a mechanism by which NK cells restrict excessive T-cell immune responses [25][26][27]. NKG2D ligand expression has also been reported in cell layers that interface with the environment, such as the gut mucosal epithelium [28,29], airway epithelial cells [30], and skin [12].…”

Section: Introductionmentioning

confidence: 99%

ULBP6/RAET1L is an additional human NKG2D ligand

Eagle¹,

Traherne²,

Hair³

et al. 2009

Eur J Immunol

107

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To date five ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) genes, encoded on human chromosome 6q24.2-q25.3, have been shown to encode ligands of the activating immunoreceptor NKG2D. Here, we show that a sixth gene, ULBP6/RAET1L, is a polymorphic locus that expresses a functional transcript. ULBP6 had a more restricted expression profile in cell lines and primary human tissues than other NKG2D ligands, but expression was detected in several human papillomavirus-positive cervical carcinoma cell lines and was inducible on infection with human CMV. ULBP6 bound to recombinant NKG2D as well as the human CMV immune evasion molecule UL16. By confocal microscopy we show that UL16 retains ULBP6 inside the cell, preventing it from reaching the cell surface. Expression of ULBP6 on target cells induced a significant increase in NK-cell killing. Comparison of ULBP6 with ULBP4 and ULBP5 indicated that differences in recombinant NKG2D binding correlated with differences in NK-cell activation.Key words: Immune evasion . Infectious diseases . Innate immunity . NK cells . NK-cell ligandsSupporting Information available online IntroductionThe stimulatory immune receptor NKG2D (NK group 2, member D) plays an important role in anti-pathogen and anti-cancer immune responses [1]. In humans, NKG2D is expressed by all NK cells and almost all abT cells and gdT cells [1]. It is normally absent from CD4 1 T cells but can be induced in some circumstances, such as in rheumatoid arthritis patients [2] and on exposure to human CMV (HCMV) [3]. NKG2D signalling function is mediated exclusively through the adaptor molecule DAP10 in humans [4], whereas mouse NKG2D can associate with both DAP10 and DAP12 [5,6]. The downstream effects of NKG2D ligation are now recognised to depend on synergy with other cell surface receptors and cytokines, with IL-15 signalling recently being shown to have a particularly close association with the NKG2D-DAP10 complex [7,8].NKG2D ligands are a diverse array of cellular proteins, all of which have structural similarity to MHC class I molecules [9]. In humans NKG2D ligands are encoded in two gene families, MIC (MHC-class-I-polypeptide related sequence) and ULBP/RAET (UL16-binding protein, also known as retinoic acid early transcript) [10][11][12][13]. We will follow the ULBP nomenclature from this point. In mouse, NKG2D ligands comprise three members of the H60 family, five members of the Rae1 (retinoic acid early inducible transcript-1) family, and Mult-1 (murine ULBP-like transcript) [14][15][16][17].According to the initial models of NKG2D function, its ligands were thought to be largely absent from healthy cells, but their expression could be induced on viral infection and on tumourigenesis [1]. Ectopic expression of NKG2D ligand leads to anticancer immune responses to transplanted tumours in mice, and the NKG2D knockout mouse has an increased susceptibility to certain types of cancer [18][19][20]. The importance of NKG2D in antiviral immune responses is illustrated by the fact that ...

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“…It has been reported that NK cells regulate T cell responses through multiple direct and indirect mechanisms, including NK cell-mediated killing of activated CD8 + T cells (14,15,(18)(19)(20)(21), CD4 + T cells (18,19,22,23), and also of dendritic cells (DCs) (12,24,25). However, little is known about a possible NK cell-mediated inhibitory/regulatory role during antitumor immune responses.…”

mentioning

confidence: 99%

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

Iraolagoitia

Spallanzani

Torres

et al. 2016

The Journal of Immunology

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Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8+ T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell–depleted mice exhibited a significantly higher frequency of SIY-specific CD8+ T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8+ T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell–depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.

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Activated, But Not Resting, T Cells Can Be Recognized and Killed by Syngeneic NK Cells

Cited by 197 publications

References 42 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

ULBP6/RAET1L is an additional human NKG2D ligand

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

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