Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis.

Tatsuki R. Kataoka,Hironori Haga,Sachiko Minamiguchi,Chiyuki Ueshima,Masahiro Hirata

doi:10.3390/ijms21030954

Tatsuki R. Kataoka, Hironori Haga + Show 3 more

Open Access

https://doi.org/10.3390/ijms21030954

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Abstract

Killer immunoglobulin-like receptor (KIR) 2DL4 (CD158d) was previously thought to be a human NK cell-specific protein. Mast cells are involved in allergic reactions via their KIT-mediated and FcɛRI-mediated responses. We recently detected the expression of KIR2DL4 in human cultured mast cells established from peripheral blood of healthy volunteers (PB-mast), in the human mast cell line LAD2, and in human tissue mast cells. Agonistic antibodies against KIR2DL4 negatively regulate the KIT-mediated and FcɛRI-mediated responses of PB-mast and LAD2 cells. In addition, agonistic antibodies and human leukocyte antigen (HLA)-G, a natural ligand for KIR2DL4, induce the secretion of leukemia inhibitory factor and serine proteases from human mast cells, which have been implicated in pregnancy establishment and cancer metastasis. Therefore, KIR2DL4 stimulation with agonistic antibodies and recombinant HLA-G protein may enhance both processes, in addition to suppressing mast-cell-mediated allergic reactions.

Highlights

Mast cells were first described by Paul Ehrlich in 1878 [1]
Gain-of-function type KIT mutations are observed in other malignancies, such as gastrointestinal stromal tumor (GIST), seminoma, and acute myelogenous leukemia (AML), though the mutated sites are varied among these malignancies [18]
KIT-mediated and FcεRI-mediated responses can be modulated by other receptors expressed on the surface of mast cells, including FcγRIIb, Siglecs, mast cell function-associated antigen, signal regulatory protein α, and leukocyte Ig-like receptor B4, paired Ig-like receptor-B, myeloid-associated immunoglobulin-like receptor I, CD200 receptor, CD300a, CD300f, Allergin-1, 2B4, CD72, programmed death-1 (PD-1), NKp46, carcinoembryonic antigen-related cell adhesion molecule 1, signaling lymphocytic activation molecule family member 8, and killer immunoglobulin-like receptor

Summary

Introduction

Mast cells were first described by Paul Ehrlich in 1878 [1]. Mast cells originate from hematopoietic precursors, and mature in almost all tissues [2,3]. Mast cell activation and their functions are regulated by cell surface receptors, among which the high-affinity receptor for IgE (FcεRI) and KIT (CD117/SCF receptor) have been studied extensively [13,14]. FcεRI expressed on mast cells consists of four subunits: an IgE-binding α chain, a β chain, and two disulfide-bonded γ chains (FcεRIγ) that are the main signal transducers Among these chains, the β chain plays key roles by amplifying the expression and signaling of FcεRI, and the followed allergic reactions via its immunoreceptor tyrosine-based activation motifs (ITAMs) [15]. Patients with mastocytosis often experience mast cell mediator-related symptoms including anaphylaxis, in addition to tissue damage caused by neoplastic mast cell infiltration [17]. Gain-of-function type KIT mutations are observed in other malignancies, such as gastrointestinal stromal tumor (GIST), seminoma, and acute myelogenous leukemia (AML), though the mutated sites are varied among these malignancies [18]

Inhibitory Receptors

KIR2DL4 Expression in Human Mast Cells

Involvement of KIR2DL4 on Human Mast Cells in the Establishment of Pregnancy

Involvement of KIR2DL4 on Human Mast Cells in Tumor Progression

KIR2DL4 as a Potent Therapeutic Target

Conclusions