Killer cell immunoglobulin-like receptor 2DL4 is expressed in and suppresses the cell growth of Langerhans cell histiocytosis.

Yusuke Takei,Chiyuki Ueshima,Akihiko Sugimoto,Tatsuki R Kataoka,Sanju Iwamoto,Kazuo Ono,Mariyo Rokutan-Kurata,Hironori Haga,Masahiro Hirata,Ichiro Murakami,Koki Moriyoshi

doi:10.18632/oncotarget.16936

Abstract

Killer cell immunoglobulin-like receptor (KIR) 2DL4 (CD158d) is a receptor for human leukocyte antigen-G. The function of KIR2DL4 has been reported in human natural killer cell lymphoma and mastocytosis, but not in Langerhans cell histiocytosis (LCH). Herein, we examined the expression and function of KIR2DL4 in LCHs. In pathological specimens, 27 of 36 LCH cases (75.0%) were immunohistochemically positive for KIR2DL4. Its expression was independent of age, gender, location, multi- or single-system, and the status of BRAFV600E immunostaining. We also confirmed the expression of KIR2DL4 mRNA and protein in the human LCH-like cell lines ELD-1 and PRU-1. KIR2DL4 protein was distributed in the membrane and cytoplasm of ELD-1 cells, but only in the cytoplasm of PRU-1 cells. An agonistic antibody against KIR2DL4 reduced phosphorylation of extracellular signal-regulated kinases (ERKs) and suppressed the cell growth of ELD-1 cells in a Src homology region 2 domain-containing phosphatase-2 dependent manner, but it had no effect in PRU-1 cells. These results suggest that KIR2DL4-mediated ERK suppression is a possible therapeutic target for LCH cells.

Highlights

Killer cell Ig-like receptors (KIRs) recognize major histocompatibility complex class I molecules and regulate human natural killer (NK) cell function both positively and negatively [1, 2]
We found that most of the Langerhans cell histiocytosis (LCH) cases were positive for KIR2DL4, suggesting that KIR2DL4 may serve as an additional marker for LCH diagnosis
In a few LCH cases, KIR2DL4 protein expression was limited to the cytoplasm

Summary

Introduction

Killer cell Ig-like receptors (KIRs) recognize major histocompatibility complex class I molecules and regulate human natural killer (NK) cell function both positively and negatively [1, 2]. The inhibitory signals by KIR2DL4 are mediated by Src homology region. The ligand of KIR2DL4 is identified as human leukocyte antigen (HLA)-G, whose expression is observed in fetal tissues during pregnancy [1, 2]. KIR2DL4 seems to be involved in the maintenance of pregnancy [8, 9]. We observed the expression of KIR2DL4 in human mast cells [10]. KIR2DL4 in human tissue mast cells enhances metastasis and invasion of HLA-G-positive cancer cells [10]. NK cell lymphoma and neoplastic mast cells (mastocytosis) express KIR2DL4 immunohistochemically [10, 11]. To the www.impactjournals.com/oncotarget best of our knowledge, the expression or role of KIR2DL4 has not been clarified in human non-NK or non-mast cell lineage malignancies

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