NKG2D Blockade Prevents Autoimmune Diabetes in NOD Mice

Ogasawara, Kunio; Hamerman, Jessica A.; Ehrlich, Lauren I.R.; Bour-Jordan, Hélène; Santamaría, Pere; Bluestone, Jeffrey A.; Lanier, Lewis L.

doi:10.1016/j.immuni.2004.05.008

Cited by 266 publications

(301 citation statements)

References 34 publications

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“…It remains to be investigated whether a high local NKG2D ligand expression also leads to a systemic NKG2D down-regulation and dysfunction or rather stimulates local immune reactions. Previous studies on rejection of NKG2DL-expressing tumor cell lines and on the role of NKG2D in the pathogenesis of diabetes in NOD mice, respectively, suggest the latter (25,26,46).…”

Section: Discussionmentioning

confidence: 95%

Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Wiemann

Mittrücker

Feger

et al. 2005

The Journal of Immunology

209

228

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The immunoreceptor NKG2D stimulates activation of cytotoxic lymphocytes upon engagement with MHC class I-related NKG2D ligands of which at least some are expressed inducibly upon exposure to carcinogens, cell stress, or viruses. In this study, we investigated consequences of a persistent NKG2D ligand expression in vivo by using transgenic mice expressing MHC class I chain-related protein A (MICA) under control of the H2-Kb promoter. Although MICA functions as a potent activating ligand of mouse NKG2D, H2-Kb-MICA mice appear healthy without aberrations in lymphocyte subsets. However, NKG2D-mediated cytotoxicity of H2-Kb-MICA NK cells is severely impaired in vitro and in vivo. This deficiency concurs with a pronounced down-regulation of surface NKG2D that is also seen on activated CD8 T cells. As a consequence, H2-Kb-MICA mice fail to reject MICA-expressing tumors and to mount normal CD8 T cell responses upon Listeria infection emphasizing the importance of NKG2D in immunity against tumors and intracellular infectious agents.

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Section: Discussionmentioning

confidence: 95%

Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Wiemann

Mittrücker

Feger

et al. 2005

The Journal of Immunology

209

228

View full text Add to dashboard Cite

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“…There is strong evidence that NK cells or NK cell receptors play an important role in the induction of autoimmune disease in this mouse strain. [40][41][42] NK cell function is dependent on the types of class I MHC receptors that are expressed on their surface. It has long been realized that in vitro NK cell function determined by cytotoxicity assays against specific tumor cell targets and in vivo responses such as bone marrow or skin graft rejection is highly dependent on mouse strain background.…”

Section: Discussionmentioning

confidence: 99%

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

et al. 2008

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The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.

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“…NKG2D has been detected in murine NK cells, CD8 + T lymphocytes and macrophages, and it has been shown to participate in the immune response against murine cytomegalovirus (MCMV) [19,57] as well as in the pathogenesis of experimental autoimmune type I diabetes [58]. The expression of NKG2D in murine effector-memory CD4 + CTL should be carefully reassessed.…”

Section: Distribution Of Ilt2 Kir and Cd94/nkg2 Nkr On Hcmv-stimulatmentioning

confidence: 99%

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

et al. 2006

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The human NKG2D killer lectin‐like receptor (KLR) is coupled by the DAP10 adapter to phosphoinositide 3‐kinase (PI3 K) and specifically interacts with different stress‐inducible molecules (i.e. MICA, MICB, ULBP) displayed by some tumour and virus‐infected cells. This KLR is commonly expressed by human NK cells as well as TCRγδ+ and TCRαβ+CD8+ T lymphocytes, but it has been also detected in CD4+ T cells from rheumatoid arthritis and cancer patients. In the present study, we analysed NKG2D expression in human cytomegalovirus (HCMV)‐specific CD4+ T lymphocytes. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from healthy seropositive individuals with HCMV promoted variable expansion of CD4+NKG2D+ T lymphocytes that coexpressed perforin. NKG2D was detected in CD28– and CD28dull subsets and was not systematically associated with the expression of other NK cell receptors (i.e. KIR, CD94/NKG2 and ILT2). Engagement of NKG2D with specific mAb synergized with TCR‐dependent activation of CD4+ T cells, triggering proliferation and cytokine production (i.e. IFN‐γ and TNF‐α). Altogether, the data support the notion that NKG2D functions as a prototypic costimulatory receptor in a subset of HCMV‐specific CD4+ T lymphocytes and thus may have a role in the response against infected HLA class II+ cells displaying NKG2D ligands.

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NKG2D Blockade Prevents Autoimmune Diabetes in NOD Mice

Cited by 266 publications

References 34 publications

Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus

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NKG2D Blockade Prevents Autoimmune Diabetes in NOD Mice

Cited by 266 publications

References 34 publications

Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Systemic NKG2D Down-Regulation Impairs NK and CD8 T Cell Responses In Vivo

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

Expression and function of NKG2D in CD4+ T cells specific for human cytomegalovirus

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Product

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Expression and function of NKG2D in CD4⁺ T cells specific for human cytomegalovirus