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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900552v1 183/2/925    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Izawa, K. Articles by Kitamura, T. PubMed PubMed Citation Articles by Izawa, K. Articles by Kitamura, T.

An Activating and Inhibitory Signal from an Inhibitory Receptor LMIR3/CLM-1: LMIR3 Augments Lipopolysaccharide Response through Association with FcR in Mast Cells¹

Kumi Izawa^*, Jiro Kitaura^*, Yoshinori Yamanishi^*, Takayuki Matsuoka^*, Ayako Kaitani^*, Masahiro Sugiuchi^*, Mariko Takahashi^*, Akie Maehara^*, Yutaka Enomoto^*, Toshihiko Oki^*, Toshiyuki Takai and Toshio Kitamura^2,*

^* Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; and the Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

Leukocyte mono-Ig-like receptor 3 (LMIR3) is an inhibitory receptor mainly expressed in myeloid cells. Coengagement of FcRI and LMIR3 impaired cytokine production in bone marrow-derived mast cells (BMMCs) induced by FcRI crosslinking alone. Mouse LMIR3 possesses five cytoplasmic tyrosine residues (Y241, Y276, Y289, Y303, Y325), among which Y241 and Y289 (Y241/289) or Y325 fit the consensus sequence of ITIM or immunotyrosine-based switch motif (ITSM), respectively. The inhibitory effect was abolished by the replacement of Y325 in addition to Y241/289 with phenylalanine (Y241/189/325/F) in accordance with the potential of Y241/289/325 to cooperatively recruit Src homology region 2 domain-containing phosphatase 1 (SHP)-1 or SHP-2. Intriguingly, LMIR3 crosslinking alone induced cytokine production in BMMCs expressing LMIR3 (Y241/276/289/303/325F) mutant as well as LMIR3 (Y241/289/325F). Moreover, coimmunoprecipitation experiments revealed that LMIR3 associated with ITAM-containing FcR. Analysis of FcR-deficient BMMCs demonstrated that both Y276/303 and FcR played a critical role in the activating function of this inhibitory receptor. Importantly, LMIR3 crosslinking enhanced cytokine production of BMMCs stimulated by LPS, while suppressing production stimulated by other TLR agonists or stem cell factor. Thus, an inhibitory receptor LMIR3 has a unique property to associate with FcR and thereby functions as an activating receptor in concert with TLR4 stimulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Ministry of Education, Science, Technology, Sports and Culture and the Ministry of Health and Welfare, Japan.

² Address correspondence and reprint requests to Dr. Toshio Kitamura, Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. E-mail address: kitamura{at}ims.u-tokyo.ac.jp

³ Abbreviations used in this paper: LMIR, leukocyte mono-Ig-like receptor; BMMC, bone marrow-derived mast cell; CLM, CMRF-35-like molecule; DAP10, DNAX activating protein of 10 kDa; IREM-1, immune receptor expressed on myeloid cells 1; ITSM, immunotyrosine-based switch motif; ODN, oligodeoxynucleotide; SHP, Src homology region 2 domain-containing phosphatase 1; SCF, stem cell factor; TNP, trinitrophenyl; WT, wild type.

⁴ The online version of this article contains supplemental material.