Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA

Bauer, Stefan; Groh, Veronika; Wu, Jun; Steinle, Alexander; Phillips, Joseph H.; Lanier, Lewis L.; Spies, Thomas A.

doi:10.1126/science.285.5428.727

Cited by 2,693 publications

(2,334 citation statements)

References 23 publications

Supporting

Mentioning

2,277

Contrasting

Unclassified

Order By: Relevance

“…Upon recognition of the stress-inducible MICA/B molecules 14 on target cells, NKG2D strongly enhances the NK-mediated cytotoxicity 14 15. Different from NCR, NKG2D is also expressed by virtually all TCR-γ/δ + as well as by CD8 + TCR-α/β + cells.…”

Section: Introductionmentioning

confidence: 99%

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Bottino

Falco

Parolini

et al. 2001

The Journal of Experimental Medicine

290

343

View full text Add to dashboard Cite

In humans, natural killer (NK) cell function is regulated by a series of receptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel member of the immunoglobulin superfamily belonging to the CD2 subfamily. NTB-A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyrosine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain–containing protein (SH2D1A) as well as with SH2 domain–containing phosphatases (SHPs). Importantly, analysis of NK cells derived from patients with X-linked lymphoproliferative disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-A can partially revert this inhibitory effect while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneously masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Bottino

Falco

Parolini

et al. 2001

The Journal of Experimental Medicine

290

343

View full text Add to dashboard Cite

show abstract

“…Ligands for NKG2D comprised human class I‐like molecules MICA, MICB, and ULBP, which are stress‐induced molecules expressed by tumors of epithelial origin and activate NK cell cytotoxicity through their NKG2D receptor 29, 30. Although we carried out immunohistochemistry using frozen sections as a preliminary experiment, evaluation of the expression of MICA, MICB, and ULBP2 in tumor tissue was challenging.…”

Section: Resultsmentioning

confidence: 99%

“…Non‐classical MHC class I antigens, such as MICA, MICB, and ULBP, can engage a stimulatory receptor on NK cells comprising a heterodimeric complex of NKG2D/DAP10, a cell‐surface adaptor molecule involved in signal transduction 29, 41. The activation signal resulting from the engagement of NKG2D‐DAP10 overrides the inhibitory signal from MHC class I molecules leading to target cell lysis 30, 42. Reportedly, high density of intratumoral NKp46‐expressing NK cells was associated with OS in CRLM patients who received neoadjuvant chemotherapy 18.…”

Section: Discussionmentioning

confidence: 99%

Effect of bevacizumab plus XELOX (CapeOX) chemotherapy on liver natural killer cell activity in colorectal cancer with resectable liver metastasis

Hirata

Ishiyama

Tanaka

et al. 2018

Annals of Gastroent Surgery

View full text Add to dashboard Cite

AimWe investigated the chemotherapy effect of resectable colorectal cancer with liver metastasis (CRLM) on the function of intrahepatic immune cells.MethodsWe classified patients into adjuvant chemotherapy (bevacizumab+CapeOX) after hepatectomy group (group A) and neoadjuvant chemotherapy followed by hepatectomy group (group B), and collected peripheral blood mononuclear cells (PBMC) and liver mononuclear cells (LMNC) to ascertain phenotypic and functional differences.ResultsThere were no significant differences in lymphocyte fractions of either PBMC or LMNC between groups, except for the significantly lower percentage of natural killer (NK) cells in LMNC in group B than in group A. Significantly higher percentage of natural‐killer group 2, member D (NKG2D)‐ positive NK cells in PBMC and percentage of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐, NKp30‐, and signal regulatory protein β (SIRPβ)‐positive NK cells in LMNC were found in group B. Furthermore, significantly higher expressions of NKG2D and SIRPβ in peripheral blood NK cells and of NKp46 and CD122 in liver NK cells were found in group B. When LMNC were incubated with interleukin (IL)‐2 in vitro, no difference was observed in the expression of these molecules in NK cells between groups. Consistently, there was no difference in the cytotoxic activity of those LMNC against a colon adenocarcinoma cell line between groups.ConclusionColorectal cancer with liver metastasis patients treated with neoadjuvant chemotherapy showed enhanced expression of activation markers on peripheral blood and liver NK cells in comparison with patients who did not receive therapy; however, the difference in those function remains unclear. These results suggest that neoadjuvant chemotherapy does not have a negative impact on intrahepatic immune cells in resectable CRLM patients.

show abstract

“…HSP70 serves in this case as a stimulatory molecule and as a target structure for NK cells. In a SCID mouse model we previously have found evidence that HSP70 can stimulate mouse NK cells to kill human tumour cells that do not express HSP70 at the cell surface but MICA/B molecules, [10] which are known ligands for the well-defined activating NK receptor NKG2D [11, 12, 31]. …”

Section: Discussionmentioning

confidence: 99%

The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells

Elsner

Flügge

Lozano

et al. 2010

J Cellular Molecular Medi

View full text Add to dashboard Cite

Although natural killer (NK) cells are often described as first line defence against infected or malignant cells which act without the need of prior activation, it is known now that the NK cell activity is tightly regulated by other cells and soluble factors. We show here that the stress-inducible heat shock protein (HSP) 70 activates human NK cells to kill target cells expressing major histocompatibility complex class I chain-related molecule A (MICA) in a natural killer group 2 member D (NKG2D-) dependent manner. The HSP70-derived peptide TKD (TKDNNLLGRFELSG) was able to replace the full-length HSP70 and to exert the same function. Interestingly, the expression of the cytotoxic effector protease granzyme B in NK cells was increased after TKD stimulation. When MICA and MICB expression was induced in human tumour cells by a histone deacetylase inhibitor and NK cells were activated by HSP70 or TKD, both treatments jointly improved the killing of the tumour cells. Thus, the synergistic activity of two stress-inducible immunological danger signals, HSP70 and MICA/B, leads to activation and enhanced cytotoxicity of human NK cells against tumour cells.

show abstract

Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA

Cited by 2,693 publications

References 23 publications

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

Effect of bevacizumab plus XELOX (CapeOX) chemotherapy on liver natural killer cell activity in colorectal cancer with resectable liver metastasis

The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells

Contact Info

Product

Resources

About