Inositol Phosphate Signaling Regulates Natural Killer Cell Development and Function

A team of immunobiologists has identified the phosphorylated IP3 (inositol trisphosphate) metabolite inositol(1,3,4,5)tetrakisphosphate (IP4) as an important novel regulator of NK (natural killer) cell development and function.

NK cells are large granular lymphocytes (LGL) that constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph node, spleen, tonsils, and thymus where they then enter into the circulation.

Investigators at The Scripps Research Institute (La Jolla, CA, USA) worked with a line of mice that had been genetically engineered to lack the gene coding for the enzyme inositol-trisphosphate 3-kinase B (ItpkB), which regulates inositol phosphate metabolism by phosphorylation of second messenger IP3 to IP4. The activity of this enzyme is responsible for regulating the levels of a large number of inositol polyphosphates that are important in cellular signaling. Itpkb regulates immune cell function and is required for T and B cell development.

In a paper published in the November 21, 2012, online edition of the journal Blood, the investigators identified a novel role for IP4 in NK cells. IP4 promoted NK cell terminal differentiation and acquisition of a mature NKR (NK receptor) repertoire. However, in mature NK cells, IP4 limited NKR induced IFNgamma (interferon gamma) secretion, granule exocytosis, and target-cell killing, in part by inhibiting the PIP3 effector-kinase Akt. The enzyme PIP3 activates downstream signaling components, the most notable one being the protein kinase AKT, which in turn activates downstream anabolic signaling pathways required for cell growth and survival.

“This is an exciting finding because it could possibly lead to the development of drugs that improve Natural Killer cell function,” said first author Dr. Karsten Sauer, associate professor of immunology and microbial science at The Scripps Research Institute. “Natural Killer cells have gained clinical interest as innovative biological therapeutics for certain cancers and also in certain infectious diseases.”

“The enzyme ItpkB has unique features that facilitate its highly specific inhibition by small molecules,” said Dr. Sauer. "Our findings suggest that such compounds could possibly be used to improve Natural Killer cell function therapeutically.”

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