Paired Ig-Like Receptors Bind to Bacteria and Shape TLR-Mediated Cytokine Production

Nakayama, Masafumi; Underhill, David; Petersen, Timothy W.; Li, Bin; Kitamura, Toshio; Takai, Toshiyuki; Aderem, Alan

doi:10.4049/jimmunol.178.7.4250

Cited by 86 publications

(93 citation statements)

References 46 publications

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“…This may be of particular importance considering the significantly higher affinity with which UL18 binds to LIR-1 compared with its endogenous ligand, and would therefore be able to outcompete MHC-I for binding. Interestingly, in addition to MHC-I and UL18, LIR-1 has also been reported to bind to a variety of bacterial species [33], however the role of these interactions during infection and whether this binding would also be sensitive to cis associations as well remains to be determined. It is important to note however that even in the presence of the cis interaction with MHC-I, binding to UL18 is limited but not absent.…”

Section: Discussionmentioning

confidence: 99%

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Uchtenhagen

et al. 2013

Eur J Immunol

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IntroductionNK cells are cytotoxic lymphocytes of the immune system, which provide innate protection against viral infection and tumor transformation [1]. NK cells eliminate altered self-cells through the direct recognition and subsequent lysis of engaged targets. The effector functions of these immune cells are dynamically regulated through the coordinated signaling of cell surface receptors that either activate or inhibit responses [2]. The stimulatory Correspondence: Dr. Deborah N. Burshtyn e-mail: burshtyn@ualberta.ca NK-cell receptors signal through coupled adaptor proteins that encode cytoplasmic ITAMs [3]. Conversely, the inhibitory receptors dampen NK-cell responses via long cytoplasmic tails encoding ITIMs, which recruit SH2 domain-containing phosphatases such as SHP-1 following tyrosine phosphorylation [4]. The inhibitory receptors typically recognize MHC class I (MHC-I) molecules, and therefore healthy self-cells expressing a full complement of MHC-I are protected from NK-cell lysis. NK cells thus sense the density of ligands on engaged cells, and it is the balance of signals received through these functionally opposing receptors that ultimately determines both the response of the effector cell and the fate of the target cell.Inhibitory MHC-I receptors expressed on human NK cells include the killer cell Ig-like receptors (KIRs) and leukocyte Ig-like C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1042-1052 Molecular immunology 1043 receptor-1 (LIR-1), which are encoded on chromosome 19q13.4 within the leukocyte receptor complex [5]. The LIR family encodes receptors with either two or four Ig domains and includes both inhibitory and activating members. While the ligands for all LIR family members have not yet been identified, the inhibitory members LIR-1 and LIR-2 bind MHC-I at the relatively conserved α3 domain and β 2 -microglobulin, allowing for broad specificity and recognition of both classical and nonclassical molecules [6,7]. NK-cell expression of LIR-1 varies between individuals and mediates inhibition of NK cells in response to MHC-I, particularly 9]. LIR-1 is also targeted by a virally encoded MHC-I homologue known as UL18 [10], which shares approximately 25% amino acid sequence identity with MHC-I and associates with human β 2 -microglobulin [11,12]. UL18 binds to LIR-1 with more than 1000-fold greater affinity than MHC-I molecules [7,13,14] and has been shown to mediate suppression of LIR-1 + NK cells in vitro [15]. Studies of LIR-1 function to date have primarily focused on the interaction of the receptor with its ligand in trans, such as inhibition of NK or T cells through recognition of a ligand expressed on a target cell or APC [16][17][18][19][20][21]. However, there is mounting evidence that the interaction of these immune receptors with ligands on the same cell, or in cis, influence how they function [22]. In the murine system, the cis interaction of MHC-I specific NK-cell receptors plays a key role in regulating NK-cell responses. The ...

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Section: Discussionmentioning

confidence: 99%

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Uchtenhagen

et al. 2013

Eur J Immunol

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“…Cells were stained with 5-(and 6-) carboxytetramethylrhodamine succinimidyl ester (TAMRA; Invitrogen) or the following mAbs: AF488-anti-I-A b , biotinylated anti-NK1.1 mAbs, and streptavidinDyLight 594 (BioLegend). Then these cells were analyzed on a Carl Zeiss LSM510 confocal laser-scanning microscope equipped with a 63× objective lens as described previously (33).…”

Section: Methodsmentioning

confidence: 99%

Natural killer (NK)–dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4⁺T cells

Nakayama¹,

Takeda

Kawano³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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102

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Natural killer (NK) cells contribute to not only innate but also to adaptive immunity by interacting with dendritic cells (DCs) and T cells. All activated human NK cells express HLA-DR and can initiate MHCII-dependent CD4 + T-cell proliferation; however, the expression of MHCII by mouse NK cells and its functional significance are controversial. In this study, we show that NK-DC interactions result in the emergence of MHCII-positive NK cells. Upon in vitro or in vivo activation, mouse conventional NK cells did not induce MHCII transcripts, but rapidly acquired MHCII protein from DCs. MHCII H2-Ab1-deficient NK cells turned I-A b -positive when adoptively transferred into wild-type mice or when cultured with WT splenic DCs. NK acquisition of MHCII was mediated by intercellular membrane transfer called "trogocytosis," but not upon DAP10/12-and MHCI-binding NK cell receptor signaling. MHCII-dressed NK cells concurrently acquired costimulatory molecules such as CD80 and CD86 from DCs; however, their expression did not reach functional levels. Therefore, MHCII-dressed NK cells inhibited DC-induced CD4 + T-cell responses rather than activated CD4 + T cells by competitive antigen presentation. In a mouse model for delayedtype hypersensitivity, adoptive transfer of MHCII-dressed NK cells attenuated footpad swelling. These results suggest that MHCIIdressed NK cells generated through NK-DC interactions regulate T cell-mediated immune responses.

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“…Mice deficient in PIR-B were also found to be hyperresponsive to chemokine signaling (55). PIR-B ITIM activation has also been shown to regulate TLR-mediated macrophage responses to some gram-positive and gram-negative bacteria (26). Other studies have shown that the SFK Lyn phosphorylates an ITIM of platelet endothelial cell adhesion molecule 1 in mast cells, leading to regulated FcεRI responses (45).…”

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confidence: 97%

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

Nelson

Metz

et al. 2009

Infect Immun

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Src family tyrosine kinases (SFKs) phosphorylate immunotyrosine activation motifs in the cytoplasmic tail of multiple immunoreceptors, leading to the initiation of cellular effector functions, such as phagocytosis, reactive oxygen species production, and cytokine production. SFKs also play important roles in regulating these responses through the activation of immunotyrosine inhibitory motif-containing inhibitory receptors. As myeloid cells preferentially express the SFKs Hck, Fgr, and Lyn, we questioned the role of these kinases in innate immune responses to Pneumocystis murina. Increased phosphorylation of Hck was readily detectable in alveolar macrophages after stimulation with P. murina. We further observed decreased phosphorylation of Lyn on its C-terminal inhibitory tyrosine in P. murina-stimulated alveolar macrophages, indicating that SFKs were activated in alveolar macrophages in response to P. murina. Mice deficient in Hck, Fgr, and Lyn exhibited augmented clearance 3 and 7 days after intratracheal administration of P. murina, which correlated with elevated levels of interleukin 1␤ (IL-1␤), IL-6, CXCL1/KC, CCL2/monocyte chemoattractant protein 1, and granulocyte colony-stimulating factor in lung homogenates and a dramatic increase in macrophage and neutrophil recruitment. Augmented P. murina clearance was also observed in Lyn ؊/؊ mice 3 days postchallenge, although the level was less than that observed in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice. A correlate to augmented clearance of P. murina in Hck ؊/؊ Fgr ؊/؊ Lyn ؊/؊ mice was a greater ability of alveolar macrophages from these mice to kill P. murina in vitro, suggesting that SFKs regulate the alveolar macrophage effector function against P. murina. Mice deficient in paired immunoglobulin receptor B (PIR-B), an inhibitory receptor activated by SFKs, did not exhibit enhanced inflammatory responsiveness to or clearance of P. murina. Our results suggest that SFKs regulate innate lung responses to P. murina in a PIR-B-independent manner.Although the advent of prophylactic therapy against Pneumocystis jirovecii alone or in combination with highly active antiretroviral therapy has reduced the incidence of pneumonia caused by this fungal pathogen, this infection remains the most prevalent opportunistic infection in individuals with AIDS (25). Furthermore, individuals receiving immunosuppressive therapies, such as individuals undergoing solid organ or hematopoietic cell transplantation, are a growing population susceptible to Pneumocystis pneumonia (34) (33). These observations warrant a more thorough examination of interactions between Pneumocystis and the host in order to define and develop new vaccine and immunotherapeutic approaches to treat Pneumocystis pneumonia.An intense area of research over the last decade is investigating how lung immune cells recognize and respond to inhaled pathogens, such as P. murina. After inhalation of P. murina into the lungs, one of the first interactions with the host is recognition by the alveolar macrophage. Our laboratory has prev...

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Paired Ig-Like Receptors Bind to Bacteria and Shape TLR-Mediated Cytokine Production

Cited by 86 publications

References 46 publications

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Natural killer (NK)–dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4⁺T cells

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

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Paired Ig-Like Receptors Bind to Bacteria and Shape TLR-Mediated Cytokine Production

Cited by 86 publications

References 46 publications

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Cis association of leukocyte Ig‐like receptor 1 with MHC class I modulates accessibility to antibodies and HCMV UL18

Natural killer (NK)–dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4+T cells

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses toPneumocystis murina

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Natural killer (NK)–dendritic cell interactions generate MHC class II-dressed NK cells that regulate CD4⁺T cells