Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells

Ehrlich, Lauren I.R.; Ogasawara, Kunio; Hamerman, Jessica A.; Takaki, Rayna; Zingoni, Alessandra; Allison, James P.; Lanier, Lewis L.

doi:10.4049/jimmunol.174.4.1922

Cited by 93 publications

(79 citation statements)

References 29 publications

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“…Similar discrepancies have been observed for resting and IL-2-activated NK cells, where several of the major activating receptors fail to stimulate resting NK cells when triggered alone [24]. Moreover, our results are in agreement with data demonstrating that NKG2D engagement by ligand or stimulatory antibodies is not sufficient to co-stimulate naive or effector CD8 1 T-cell responses in conventional T-cell populations [32].…”

Section: Discussionsupporting

confidence: 91%

Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

et al. 2010

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Effector T‐cell responses can be modulated by competing positive or negative signals transduced by NK‐cell receptors (NKR). In the CD4+ T‐cell population, the expression of NKR is primarily found in the CD4+CD28− T‐cell subset, also known as CD28null T cells. These T cells are frequently found in rheumatoid arthritis (RA) and other inflammatory disorders, suggesting that signaling through NKR may play a role in the autoimmune reaction. Here we aimed to dissect the phenotype and function of NKR‐expressing CD4+CD28− T cells in patients with RA. By analyzing a broad array of NKR on CD4+CD28− T cells we found a significant expression of the co‐activating receptors 2B4 (CD244), DNAM‐1 (CD226), and CRACC. Pair‐wise ligations of 2B4 with DNAM‐1 and/or NKG2D lead to increased effector functions of primary CD4+CD28− T cells to suboptimal levels of anti‐CD3 stimulation. Using multi‐parameter flow cytometry, we demonstrate that such co‐ligation led to an increased magnitude in overall responsiveness without changing qualitative aspects of the response. Altogether these results demonstrate a pattern of additive effects in NKR‐mediated functional modulation of CD4+CD28− T cells in RA. This may have consequences for the inflammatory responses imposed by these cells, thus influencing disease manifestations.

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Section: Discussionsupporting

confidence: 91%

Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

et al. 2010

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“…The engagement of NKG2D resulted in enhanced CTL expansion, IFN-␥ secretion, and CTL activity, suggesting that NKG2D is a costimulatory molecule sharing functional similarities with CD28 (60). These findings differ from those of Ehrlich et al (25), in which a rigorous analysis indicated that NKG2D expression on mouse CD8 ϩ T cells acts as a costimulatory molecule only under restricted conditions or requires additional cofactors. The experimental conditions and model systems employed may explain the differences between these results.…”

Section: Discussioncontrasting

confidence: 56%

“…During priming, naïve CD8 ϩ T cells require T-cell receptor (TCR) engagement to MHC molecules presenting antigenic peptide and secondary costimulatory signals, such as CD28 ligation by members of the B7 family, in order to expand and differentiate into CTLs (88). Importantly, the costimulation of antigen-primed CTLs is not required for the release of effector molecules, but it can enhance effector functions (25,51,60). T cells express numerous receptors that act in controlling cellular responses through recognition and binding to specific ligands (88).…”

Section: Discussionmentioning

confidence: 99%

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

Walsh

Lanier

Lane

2008

J Virol

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Inoculation with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of mice results in an acute encephalitis associated with an immune-mediated demyelinating disease. During acute disease, infiltrating CD8 ؉ T cells secrete gamma interferon (IFN-␥) that controls replication in oligodendrocytes, while infected astrocytes and microglia are susceptible to perforin-mediated lysis. The present study was undertaken to reveal the functional contributions of the activating NKG2D receptor in host defense and disease following JHMV infection. NKG2D ligands RAE-1, MULT1, and H60 were expressed within the CNS following JHMV infection. The immunophenotyping of infiltrating cells revealed that NKG2D was expressed on ϳ90% of infiltrating CD8 ؉ T cells during acute and chronic disease. Blocking NKG2D following JHMV infection resulted in increased mortality that correlated with increased viral titers within the CNS. Anti-NKG2D treatment did not alter T-cell infiltration into the CNS or the generation of virus-specific CD8 ؉ T cells, and the expression of IFN-␥ was not affected. However, cytotoxic T-lymphocyte (CTL) activity was dependent on NKG2D expression, because anti-NKG2D treatment resulted in a dramatic reduction in lytic activity by virus-specific CD8 ؉ T cells. Blocking NKG2D during chronic disease did not affect either T-cell or macrophage infiltration or the severity of demyelination, indicating that NKG2D does not contribute to virus-induced demyelination. These findings demonstrate a functional role for NKG2D in host defense during acute viral encephalitis by selectively enhancing CTL activity by infiltrating virus-specific CD8 ؉ T cells.Viral infection of the central nervous system (CNS) presents unique challenges to the immune system with regard to controlling and eliminating the invading pathogen. These obstacles include the presence of a blood-brain barrier that provides a physical and physiological barrier that is difficult for cells and molecules to cross, the absence of classic lymphatic drainage that may impair the generation of an adaptive immune response, and the relative absence of major histocompatibility complex (MHC) class I or II expression on resident cells (3,26,39,73). In addition, the CNS is composed of a variety of highly specialized cells, many of which have limited renewal capacity, that represent potential targets of infection by numerous different viruses (34, 81). Therefore, a significant hurdle encountered by infiltrating antigen-specific lymphocytes is the elimination of virus from infected cells while limiting the damage that may have long-term detrimental consequences to the host. Critical to this is the cellular tropism of the virus, as this is important in dictating the effector response by infiltrating lymphocytes. For example, neuronotropic viruses often are eliminated by noncytolytic mechanisms via cytokine-mediated control and/or neutralizing antibodies, whereas the infection of other cell populations can evoke cytolytic mechanisms for c...

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“…In contrast, the concomitant down-regulation of H60 and up-regulation of MHC class I proteins on tumor cells would effectively convert them from NK cell targets to CD8 ϩ T cell targets. Although some studies have shown a positive role for murine NKG2D receptor-ligand interactions in costimulating CD8 ϩ T cell proliferation and cytotoxicity (17,48), other studies have found no role for this ligand-receptor system in affecting T cell function (49) and some even report that certain NKG2D ligands can inhibit CD8 ϩ T cell function in an NKG2D-independent manner (50). Indeed, our preliminary finding is that IFN-␥ treatment of the F244 sarcoma line enhanced its recognition by a T cell line while inhibiting its recognition by NK cells (J. D. Bui and R. D. Schreiber, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

IFN-Dependent Down-Regulation of the NKG2D Ligand H60 on Tumors

Bui

Carayannopoulos

Lanier

et al. 2006

The Journal of Immunology

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In this study, we show that IFN-γ or IFN-α reduce expression of H60 on 3′-methylcholanthrene (MCA) sarcomas from 129/Sv mice. As determined by flow cytometry using either NKG2D tetramers or NKG2D ligand-specific mAb, H60 was identified as the NKG2D ligand most frequently expressed on these sarcomas, and its expression was selectively down-regulated by either IFN-γ or IFN-α in a manner that was dose- and time-dependent and reversible. Down-regulation occurred at the transcript level and was STAT1-dependent. It also had functional consequences. IFN-γ-treated MCA sarcomas with high levels of H60 were resistant to killing by IL-2-activated NK cells. Resistance was not solely dependent on enhanced MHC class I expression but rather also required H60 down-regulation. IFN-γ-treated tumor cells also displayed diminished capacity to down-regulate NKG2D on freshly isolated NK cells. Transplanted tumor cells reisolated from immunocompetent mice displayed reduced H60 expression and increased MHC class I expression compared with tumor cells that were either left unmanipulated or reisolated from mice treated with neutralizing IFN-γ-specific mAb. This report thus represents the first demonstration that certain cytokines and specifically the IFNs regulate expression of specific NKG2D ligands on murine tumors. This process most likely helps to specify the type of immune effector cell populations that participate in host-protective antitumor responses.

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Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells

Cited by 93 publications

References 29 publications

Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

IFN-Dependent Down-Regulation of the NKG2D Ligand H60 on Tumors

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Engagement of NKG2D by Cognate Ligand or Antibody Alone Is Insufficient to Mediate Costimulation of Human and Mouse CD8+ T Cells

Cited by 93 publications

References 29 publications

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8+T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis

IFN-Dependent Down-Regulation of the NKG2D Ligand H60 on Tumors

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Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

Activating NK‐cell receptors co‐stimulate CD4⁺CD28⁻ T cells in patients with rheumatoid arthritis

NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8⁺T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis