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NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease.

ABSTRACT: Deficiencies of the T cell and NK cell CD3? signaling adapter protein in patients with cancer and autoimmune diseases are well documented, but mechanistic explanations are fragmentary. The stimulatory NKG2D receptor on T and NK cells mediates tumor immunity but can also promote local and systemic immune suppression in conditions of persistent NKG2D ligand induction that include cancer and certain autoimmune diseases. In this paper, we provide evidence that establishes a causative link between CD3? impairment and chronic NKG2D stimulation due to pathological ligand expression. We describe a mechanism whereby NKG2D signaling in human T and NK cells initiates Fas ligand/Fas-mediated caspase-3/-7 activation and resultant CD3? degradation. As a consequence, the functional capacities of the TCR, the low-affinity Fc receptor for IgG, and the NKp30 and NKp46 natural cytotoxicity receptors, which all signal through CD3?, are impaired. These findings are extended to ex vivo phenotypes of T and NK cells among tumor-infiltrating lymphocytes and in peripheral blood from patients with juvenile-onset lupus. Collectively, these results indicate that pathological NKG2D ligand expression leads to simultaneous impairment of multiple CD3?-dependent receptor functions, thus offering an explanation that may be applicable to CD3? deficiencies associated with diverse disease conditions.

SUBMITTER: Hanaoka N

PROVIDER: S-EPMC3044081 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease.

Hanaoka Nobuyoshi N Jabri Bana B Dai Zhenpeng Z Ciszewski Cezary C Stevens Anne M AM Yee Cassian C Nakakuma Hideki H Spies Thomas T Groh Veronika V

Journal of immunology (Baltimore, Md. : 1950) 20101006 10

Deficiencies of the T cell and NK cell CD3ζ signaling adapter protein in patients with cancer and autoimmune diseases are well documented, but mechanistic explanations are fragmentary. The stimulatory NKG2D receptor on T and NK cells mediates tumor immunity but can also promote local and systemic immune suppression in conditions of persistent NKG2D ligand induction that include cancer and certain autoimmune diseases. In this paper, we provide evidence that establishes a causative link between CD ...[more]

PMID: 20926796

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Project description:Large granular lymphocyte leukemia is a semi-autonomous clonal proliferation of cytotoxic T cells accompanied by immune cytopenias and various autoimmune conditions. Due to the rarity of this disease and its association with autoimmune diseases, a theoretical germline or somatic mutation might have significant penetrance, thus enabling detection, even from samples of suboptimal size, through genome-wide association studies.To investigate a non-mendelian genetic predisposition to large granular lymphocyte leukemia, we used a step-wise method for gene discovery. First, a modified 'random forests' technique was used for candidate gene identification: this was followed by traditional allele-specific polymerase chain reaction, sequencing modalities, and mechanistic assays.Our analysis found an association with MICA, a non-peptide-presenting, tightly regulated, stress-induced MHC-like molecule and cognate receptor for NKG2D, found abundantly on large granular lymphocyte leukemia cells. Sequencing of germline DNA revealed a higher frequency of MICA*00801/A5.1 in patients with large granular lymphocyte leukemia than in matched controls (64% versus 41%, P<0.001, homozygous 40% versus 15%, P<0.001). Flow cytometry was employed to determine the expression of MICA within hematologic compartments, showing that the signal intensity of MICA was increased in granulocytes from neutropenic patients with large granular lymphocyte leukemia in comparison with that in controls (P=0.033). Furthermore, neutrophil counts were inversely correlated with MICA expression (R(2)=0.50, P=0.035). Finally, large granular lymphocyte leukemia cells were able to selectively kill MICA(+) Ba/F3 lymphocytes transfected with human MICA*019 in a dose-dependent manner compared to naïve cells (P<0.001), an effect mitigated by administration of an anti-NKG2D antibody (P=0.033).Our results illustrate that MICA-NKG2D played a role in disease pathogenesis in the majority of patients in our cohort of cases of large granular lymphocyte leukemia and further investigation into this signaling axis may provide potent therapeutic targets.

Dataset Information

NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease.

Publications

NKG2D initiates caspase-mediated CD3zeta degradation and lymphocyte receptor impairments associated with human cancer and autoimmune disease.

Similar Datasets

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