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Functional and developmental heterogeneity of invariant natural killer T cells

February 8, 2012 PRESS RELEASE

Allergy has become one of the most prevalent diseases in Japan, affecting 30% of the population. Atopic asthma is one of the more serious allergic diseases and it afflicts 300 million people worldwide, causing 250 thousand deaths every year. The numbers are increasing; childhood asthma is found in 6% of children these days, six times more than in the 1980’s.

A research team lead by Masaru Taniguchi and Hiroshi Watarai (Group Director and Senior Researcher, respectively, at the Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology) had previously identified a subtype of Natural Killer T (NKT) cells expressing IL-17 receptor B (IL-17RB+) that triggers the pathogenesis in airway hyper reactivity, an animal model for asthma (J. Exp. Med., Vol. 25, 2727-2733, 2008). IL-17RB+ NKT cells produce IL-4, IL-5, IL-13, IL-17A and IL-22, cytokines that cause airway inflammation and damage bronchial mucosa. In further investigating this NKT subtype, they recently discovered that there are distinct developmental lineages and functions among NKT cells (Figure).

It is known that NKT cells change their cell surface marker expression patterns during development; NKT cells develop through Stage 1 (CD44- NK1.1-), Stage 2 (CD44+ NK1.1-) and Stage 3 (CD44+ NK1.1+) in the thymus and then move to the periphery. When the team analyzed the expression of IL-17RB in mouse thymus, they found that only 10% of thymic NKT cells were IL-17RB+, and most of them were in Stage 1 and 2. Surprisingly, these IL-17RB+ NKT cells did not require IL-15, which, until now, was thought to be essential for NKT cell maturation. IL-17RB+ NKT cells maturated from Stage 1 to Stage 2 and then, without changing to IL-17RB-, they moved to the periphery. This observation suggested that IL-17RB+ cells constitute a distinct NKT subtype, one which follows a different developmental pathway from the IL-17RB- NKT cells. Based on cytokine production, two distinct subpopulations of IL-17RB+ NKT cells could be identified, IL-17RB+CD4+ and IL-17RB+CD4- NKT cells. IL-17RB+CD4+ NKT cells responded to IL-25 and produced TH2 cytokines (IL-13, IL-4), TH9 cytokines (IL-9, IL-10) and TH17 cytokines (IL-17A, IL-22), while IL-17RB+CD4- NKT cells responded to IL-23 and produced TH17 cytokines (IL-17A, IL-22). These cytokines are known to induce allergic reactions directly but also to stimulate other immune cells and cause inflammation.

Given this developmental heterogeneity, the team next analyzed in vivofunctions of IL-17RB+ NKT cells. They found that the allergy prone BALB/c mouse strain had 3-4 fold more IL-17RB+ NKT cells than the less allergic C57BL/6 strain. Indeed, Il17rb knockout mice had a defective production of TH2, TH9, and TH17 cytokines, and when they were infected with respiratory syncytial virus (RSV), which causes bronchitis and pneumonia, Il17rb knockout mice did not develop any airway inflammation. “IL-17RB+ NKT cells were responsible for exacerbating the inflammation caused by RSV infection. RSV infection is one of the major causes of pneumonia in asthmatic babies and children. Regulation of IL-17RB+ NKT cells would be a key for prevention of inflammation in childhood asthma,” said Hiroshi Watarai.

This research was supported by Japan Science and Technology Agency’s Precursory Research for Embryonic Science and Technology (PRESTO).

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(Figure) Newly proposed model of NKT cell development and function

<Related information>
  • Original paper:
    Hiroshi Watarai, Etsuko Sekine-Kondo, Tomokuni Shigeura, Yasutaka Motomura, Takuwa Yasuda, Rumi Satoh, Hisahiro Yoshida, Masato Kubo, Hiroshi Kawamoto, Haruhiko Koseki and Masaru Taniguchi. Development and Function of Invariant Natural Killer T Cells Producing TH2- and TH17-Cytokines. PLoS Biol. Vol. 10, e1001255, 2012.
  • Related paper:
    Asuka Terashima, Hiroshi Watarai, Sayo Inoue, Etsuko Sekine, Ryusuke Nakagawa, Koji Hase, Chiaki Iwamura, Hiroshi Nakajima, Toshinori Nakayama, and Masaru Taniguchi. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J. Exp. Med., Vol. 25, 2727-2733, 2008.