Cis Binding Between Inhibitory Receptors and MHC Class I Can
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ARTICLE Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation Ai Masuda, Akira Nakamura, Tsutomu Maeda, Yuzuru Sakamoto, and Toshiyuki Takai Department of Experimental Immunology and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Institute of Development, Aging and Cancer, Tohoku University, Aoba-ku, Sendai-shi 980-8575, Japan Downloaded from http://rupress.org/jem/article-pdf/204/4/907/1399116/jem_20060631.pdf by guest on 02 October 2021 Allergy is caused by immune effector cells, including mast cells and basophils. Cellular signaling that activates these effector cells is regulated by different inhibitory receptors on their surface. We show that human leukocyte immunoglobulin (Ig)-like receptor (LILR) B2 and its mouse orthologue, paired Ig-like receptor (PIR)–B, constitutively associate to major histocompatibility complex (MHC) class I on the same cell surface (in cis). The IgE-mediated β β effector responses were augmented in 2-microglobulin ( 2m) and PIR-B–defi cient mast β cells. In addition, the increased cytokine production of 2m-defi cient mast cells was not affected by the co-culture with MHC class I–positive mast cells, showing that less cis interaction between PIR-B and MHC class I on mast cells led to the increased cytokine release. Thus, the constitutive cis binding between LILRB2 or PIR-B and MHC class I has an essential role in regulating allergic responses. CORRESPONDENCE Mast cells and basophils, which are derived Toll-like receptors, as well as those for comple- Toshiyuki Takai: from hematopoietic progenitor cells, are key ment components like cytokines and chemo- [email protected] eff ector cells in IgE-mediated immune re- kines (2, 3). These receptors can also activate Abbreviations used: BMMC, sponses, such as allergy and host protection mast cells or basophils upon binding to their bone marrow–derived mast cell; against parasites (1–4). Upon binding of the an- cognate ligands, resulting in the de novo syn- β β ε 2m, 2-microglobulin; Fc RI, tigen to IgE, these eff ector cells immediately thesis and release of cytokines, chemokines, high affi nity FcR for IgE; FcγRIIB and FcγRIII, type IIB release various proinfl ammatory molecules, in- and lipid mediators (1–4). Upon stimulation by and type III, respectively, low cluding chemical mediators and cytokines (1–4). these activating receptors, mast cells or baso- affi nity FcR for IgG; FRET, These cells express high affi nity FcR for IgE phils are triggered within a few minutes, thus fl uorescence resonance energy ε transfer; HRP, horseradish (Fc RI), which is composed of an IgE-binding leading to acute hypersensitive responses, such peroxidase; ITAM, immuno- α subunit, a β subunit (FcεRIβ), and a disul- as anaphylaxis and acute asthma attack (4). The Journal of Experimental Medicine receptor tyrosine–based activation phide-bonded γ subunit (FcRγ) homodimer Moreover, the constitutive binding of mono- motif; ITIM, immunoreceptor (4, 5). Both FcRγ and FcεRIβ contain a cyto- meric IgE molecules to FcεRI can amplify tyrosine–based inhibition motif; ε LILR, leukocyte Ig-like receptor; plasmic amino acid sequence termed immuno- cell-surface expression of Fc RI and its sig- MIP, macrophage infl ammatory receptor tyrosine–based activation motif (ITAM) naling (1, 4, 6). protein; PIR, paired (4, 5). Upon clustering of FcεRI by IgE and Considering the presence of diff erent ways Ig-like receptor; PLC, phospho- lipase C; PMT, photomultiplier; multivalent antigens, the intracellular Src family to stimulate mast cell or basophil activation cas- SHP, Src homology domain 2– protein tyrosine kinases phosphorylate tyrosine cades, one may predict the importance of the containing tyrosine phosphate; residues of the ITAMs of FcRγ and FcεRIβ counterregulatory system of mast cells or baso- SIRP, signal regulatory protein. (4, 5). The phosphorylated ITAM serves as the phils, which tightly suppress any spontaneous binding site for Syk, resulting in its activation or excessive activation of the cells. In fact, like and autophosphorylation, which leads to the other cells in the immune system, mast cells induction of a further downstream signaling and basophils express various inhibitory recep- cascade (4). Mast cells and basophils also ex- tors, which counteract activating receptors press other ITAM-bearing receptors, such as on the same cells (7). In mice, these include type III low affi nity FcR for IgG (FcγRIII), FcγRIIB (7, 8), mast cell function–associated and many activating-type receptors, including antigen (9), and gp49B (10), all of which harbor one or more immunoreceptor tyrosine–based A. Masuda and A. Nakamura contributed equally to this work. inhibitory motifs (ITIMs) in their cytoplasmic JEM © The Rockefeller University Press $15.00 907 Vol. 204, No. 4, April 16, 2007 907–920 www.jem.org/cgi/doi/10.1084/jem.20060631 portions. When coengaged with activating-type receptors of whether cells expressing PIRs or LILRs, such as mast cells such as FcεRI, the tyrosine residues in these ITIMs of the and basophils, could be autoregulated by the MHC class I mol- inhibitory receptors are phosphorylated (1, 7) and recruit ecules expressed on their own (in cis) or influenced by Src homology domain 2–containing inositol polyphosphate the self-marker molecules on the surrounding cells (in trans), 5′-phosphatase (1, 7) or Src homology domain 2–containing or both. Clarifying this question should be fundamentally im- tyrosine phosphate (SHP)–1 (1, 7), both of which dephos- portant, because it will provide us with an invaluable notion phorylate the ITAM-induced signaling molecules. There- of the mode of regulation in MHC class I and its receptors, fore, mast cells lacking these inhibitory receptors are sensitive which probably constitute pivotal components maintaining to IgE stimulation (7). In contrast, mast cells lacking acti- peripheral tolerance. As predicted by the missing-self hy- vating receptors show attenuated responses to various stim- pothesis (26), various inhibitory receptors for MHC class I ulation, indicating that the mast cell activation is regulated molecules have been identifi ed in NK cells and T cell subsets by adequate balancing between activating and inhibitory (27–29), such as killer Ig-like receptors (30), CD94/NKG2A receptors (1–4, 7). heterodimers (31), and the C-type lectin superfamily, includ- Leukocyte Ig-like receptors (LILRs) are a family of Ig- ing mouse Ly49 receptors (32). In the NK cell case, trans Downloaded from http://rupress.org/jem/article-pdf/204/4/907/1399116/jem_20060631.pdf by guest on 02 October 2021 like receptors encoded by several genes and are expressed on regulation has been verifi ed to be important, because MHC various immune cells, such as those of myeloid and lymphoid class I on surrounding cells is monitored through their inhibi- lineages (11, 12). LILRs are divided into two types of receptors: tory MHC class I receptors that suppress NK cell–mediated activating-type receptors (LILRA1–A6) and inhibitory-type cytotoxicity against class I–bearing normal cells and target ab- receptors (LILRB1–B5). Activating-type LILRs, which as- normal cells that do not suffi ciently express MHC class I, sociate with FcRγ, deliver positive signals into the cells, such as virus-infected cells (27, 29). Recent analysis on mouse whereas inhibitory-type LILRs harbor ITIMs in their cyto- Ly49A suggested the consequences of both cis and trans inter- plasmic portions and deliver inhibitory signaling by re- actions between Ly49A and its ligand H-2Dd for the optimal cruiting SHP-1 to the phosphotyrosylated ITIMs (11, 12). regulation of NK cells (33). However, little is known about Although it remains unclear whether LILRs are expressed on the mode of regulation for other MHC class I–recognizing mast cells, peripheral basophils express several LILRs, such as receptors such as LILRs on other immune cells, including LILRA2, LILRB2, and LILRB3 proteins (13). Recent stud- basophils. In particular, mechanisms of PIRs and the MHC ies demonstrated that LILRA2 can elicit eff ector functions of class I binding in mast cell regulation remain to be clarifi ed, basophils upon cross-linking with antibodies (13). Moreover, although the possible signifi cance of PIR-B in allergic reac- LILRB2 represses the basophil activation stimulated with tions has been suggested, because Th2 cell–skewed immune IgE or anti-LILRA2 (13), showing that LILRs have an es- responses, in terms of increased IL-4 production and enhanced sential role in the function of basophils. Although a full IgG1 and IgE production, were seen in PIR-B–defi cient spectrum of the ligands for LILRs is not yet clarifi ed, several (Pirb−/−) mice in response to immunization with thymus- LILRs are found to recognize MHC class I molecules as their dependent antigens (34). ligands (12, 14). In particular, LILRB1 and LILRB2 can bind In this paper, we demonstrate the physiologic importance various classical or nonclassical MHC class I without allele of constitutive cis association between LILRB2 or PIR-B specifi city (14). and MHC class I on human basophilic cell lines or mouse Mouse LILR relatives or orthologues, paired Ig-like re- mast cells, respectively. In particular, mast cells from either −/− β ceptors (PIRs) (15, 16) are also composed of two isoforms, Pirb mice or MHC class I–defi cient 2-microglobulin β −/− activating PIR-A and inhibitory PIR-B, expressed on vari- ( 2m)–defi cient (B2m ) mice and these animals themselves ous hematopoietic cell lineages, including B cells, mast cells, revealed similar profi les upon stimulation, namely IgE- and macrophages, granulocytes, and DCs, but are not expressed FcεRI-mediated degranulation, cytokine and lipid mediator on T cells and NK cells (16, 17). PIR-A requires ITAM- release, and systemic anaphylaxis. These results show the es- containing FcRγ for its cell-surface expression and signal sential role of the self-recognizing PIR-B or LILRB2 system transduction (17–21).