Impaired NK Cytolytic Activity and Enhanced Tumor Growth in NK Lytic-Associated Molecule-Deficient Mice

Abstract

NK lytic-associated molecule (NKLAM) is a protein involved in the cytolytic function of NK cells. It is weakly expressed in resting NK cells but upon target cell stimulation or after incubation with cytokines that enhance NK killing, NKLAM mRNA levels increase and protein is synthesized and is targeted to cytoplasmic granule membranes. We have previously shown that NKLAM plays a role in perforin/granzyme-mediated cytolysis in vitro. To further investigate the function of NKLAM in NK cell-mediated cytotoxicity, we generated, by gene targeting, NKLAM-deficient mice. These mice have normal numbers of NK cells and other lymphoid populations in the spleen. They also have no alterations in NK maturation or NK receptor repertoire. NK cells from NKLAM-deficient and WT mice have comparable amounts of perforin, granzyme B, and lysosomal membrane-associated protein 1 (CD107a) in their cytotoxic granules and comparable levels of granule exocytosis are induced by PMA and calcium ionophore A23187. However, NKLAM-deficient NK cells display significantly less NK cytotoxic activity in vitro than WT NK cells. They also secrete less IFN-γ upon target cell stimulation, In addition, NKLAM-deficient mice exhibit greater numbers of pulmonary metastases after i.v. injection with B16 melanoma cells. These studies indicate that NKLAM-deficient mice have diminished capacity to control tumor metastases and support the role for NKLAM in NK function both in vitro and in vivo.

Interferon response factor 3 is crucial to poly-I:C induced NK cell activity and control of B16 melanoma growth

“…Data from several labs indicate that expression of GrB [36] and IFN-γ [37] are critical factors in the anti-tumor effect of activated NK cells. Therefore, splenic mononuclear cells from C57Bl/6 and IRF3KO mice were treated with poly I:C in vitro and after 24 h, CD49b + NK cells were examined by FACS analysis for intracellular GrB and IFN-γ.…”

Identification of Host Genes Linked with the Survivability of Chickens Infected with Recombinant Viruses Possessing H5N1 Surface Antigens from a Highly Pathogenic Avian Influenza Virus

“…As a higher expression of the USP18 gene was seen in chickens with a shorter survival period, induction of the gene as a direct effect of infection with a highly pathogenic virus was considered possible. On the contrary, of the genes correlating with survivability, RNF19B was considered to interact with HbcH8, which plays a similar role as E2 in the ISG15 system and might act as E3 in the ISG15 system (5,9,12,22). RNF19B would play a conflicting role against USP18 in the ISG15 system, as it increases the conjugates of the target proteins and ISG15.…”

E3 ubiquitin ligase NKLAM ubiquitinates STAT1 and positively regulates STAT1-mediated transcriptional activity

“…IFNγ) and bacterial products such as lipopolysaccharide (LPS) [4]. Studies from our laboratory have demonstrated that NK cells from NKLAM-knock out (NKLAM-KO) mice have diminished anti-tumor activity [5]. Additionally, we have shown that NKLAM plays a role in controlling tumor metastasis [6].…”