Receptors and lytic mediators regulating anti-tumor activity by the leukemic killer T cell line TALL-104

175

143

Elimination of influenza virus-infected cells during primary influenza virus infections is thought to be mediated by CD8+ T cells though perforin- and FasL-mediated mechanisms. However, recent studies suggest that CD8+ T cells can also utilize TRAIL to kill virally infected cells. Therefore, we herein examined the importance of TRAIL to influenza-specific CD8+ T cell immunity and to the control of influenza virus infections. Our results show that TRAIL deficiency increases influenza-associated morbidity and influenza virus titers, and that these changes in disease severity are coupled to decreased influenza-specific CD8+ T cell cytotoxicity in TRAIL−/− mice, a decrease that occurs despite equivalent numbers of pulmonary influenza-specific CD8+ T cells. Furthermore, TRAIL expression occurs selectively on influenza-specific CD8+ T cells, and high TRAIL receptor (DR5) expression occurs selectively on influenza virus-infected pulmonary epithelial cells. Finally, we show that adoptive transfer of TRAIL+/+ but not TRAIL−/− CD8+ effector T cells alters the mortality associated with lethal dose influenza virus infections. Collectively, our results suggest that TRAIL is an important component of immunity to influenza infections and that TRAIL deficiency decreases CD8+ T cell-mediated cytotoxicity, leading to more severe influenza infections.

Section: Discussionmentioning

confidence: 93%

CD8 T Cells Utilize TRAIL to Control Influenza Virus Infection

Brincks

Katewa

Kucaba³

et al. 2008

175

143

“…Although mainly NK cell-associated, CD16 and the NCRs are also expressed by some T cells (43, 44). Whereas CD16, NKp30, and NKp46 are either absent or poorly expressed in TALL-104 cells (45), three of the eight NKG2D-licensed T cell lines were strongly positive for NKp46 (lines 1, 3, and 6), and one of those (line 3) also expressed CD16. We thus tested these T cell lines in redirected cytotoxicity assays for CD16 and NKp46 functions after NKG2D-initiated CD3ζ downmodulation.…”

Section: Resultsmentioning

confidence: 99%

NKG2D Initiates Caspase-Mediated CD3ζ Degradation and Lymphocyte Receptor Impairments Associated with Human Cancer and Autoimmune Disease

Hanaoka

Jabrì

Dai

et al. 2010

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 CD3ζ 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 CD3ζ 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 CD3ζ, 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 CD3ζ-dependent receptor functions, thus offering an explanation that may be applicable to CD3ζ deficiencies associated with diverse disease conditions.

“…Early work defined a specific receptor-ligand pairing between KIR3DL2 and HLA-A*03/-A*11, presumably as complex with bound peptide, and not other MHC-I allotypes (36–38). In addition, studies with HLA-A*03 tetramers and KIR3DL2 transfectants suggested that tetramer binding was dependent on the peptide used to form the tetramer (39).…”

Section: Discussionmentioning

confidence: 99%

HLA-F and MHC Class I Open Conformers Are Ligands for NK Cell Ig-like Receptors

Goodridge

Burian

Lee

et al. 2013

117

109

Killer Immunoglobulin-like receptors (KIR) are innate immune receptors expressed by NK and T cells classically associated with the detection of missing-self through loss of their respective MHC ligand. Some KIR specificities for allelic classical class I MHC (MHC-I) have been described, while other KIR receptor-ligand relationships, including those associated with non-classical MHC-I, have yet to be clearly defined. We report here that KIR3DL2 and KIR2DS4 and the non-classical antigen HLA-F, expressed as a free form devoid of peptide, physically and functionally interact. These interactions extend to include classical MHC class I open conformers as ligands, defining new relationships between KIR receptors and class I MHC. The data collectively suggest a broader, previously unrecognized interaction between MHC-I open conformers – including prototypical HLA-F – and KIR receptors, acting in an immunoregulatory capacity centered on the inflammatory response.