The immunosuppressive effect of domain-deleted dimer of HLA-G2 isoform in collagen-induced arthritis mice

Takahashi, Ami; Kuroki, Kazuhiko; Okabe, Yuki; Kasai, Yoshiyuki; Matsumoto, Naoki; Yamada, Chizumi; Takai, Toshiyuki; Ose, Toyoyuki; Kawa, Shigeyuki; Matsuda, Tadashi; Maenaka, Katsumi

doi:10.1016/j.humimm.2016.01.010

Cited by 16 publications

(22 citation statements)

References 23 publications

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“…In this study, we prepared functional rHLA-G2, which exhibited specific binding to LILRB2 in vitro ( Fig. 3) and an antiinflammatory effect in vivo (8). Furthermore, the EM structure of HLA-G2 is in good agreement with the fit for the HLA-G1 a1 and a3 domains without the Cys 42 -Cys 42 disulfide bond.…”

Section: Hla-g2 Proteins Bind To Lilrb2 With a Notable Avidity Effectmentioning

confidence: 55%

“…This is supported by the observations of the existence of healthy individuals who do not have HLA-G1 and who, therefore, would be predicted only to have HLA-G2 forms capable of binding to LILRB2. In a previous study, we demonstrated the significant immunosuppressive effects of the HLA-G1 monomer/homodimer and HLA-G2 in a CIA mice model (3,8). In terms of receptor distribution, paired Ig-like receptor B (mouse) and LILRB2 FIGURE 3.…”

Section: Hla-g2 Proteins Bind To Lilrb2 With a Notable Avidity Effectmentioning

confidence: 93%

“…HLA-G2-transfected cells were protected from killing by NK cells and CTLs in vitro (7). Recently, we reported the significant immunosuppressive effect of rHLA-G2 protein in CIA mice (8). Because it lacks an a2 domain, the HLA-G2 isoform is expected not to associate with b2-microglobulin (b2m) and to form a disulfide-linked homodimer via Cys 42 (9), like HLA-G1; however, structural data on HLA-G2 that could confirm this have not been available.…”

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confidence: 98%

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Cutting Edge: Class II–like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

Kuroki

Mio

Takahashi

et al. 2017

The Journal of Immunology

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HLA-G is a natural tolerogenic molecule and has the following unique features: seven isoforms (HLA-G1 to HLA-G7), formation of disulfide-linked homodimers, and β2-microglobulin (β2m)-free forms. Interestingly, individuals null for the major isoform, HLA-G1, are healthy and expressed the α2 domain-deleted isoform, HLA-G2, which presumably compensates for HLA-G1 function. However, the molecular characteristics of HLA-G2 are largely unknown. In this study, we unexpectedly found that HLA-G2 naturally forms a β2m-free and nondisulfide-linked homodimer, which is in contrast to the disulfide-bonded β2m-associated HLA-G1 homodimer. Furthermore, single-particle analysis, using electron microscopy, revealed that the overall structure and domain organization of the HLA-G2 homodimer resemble those of the HLA class II heterodimer. The HLA-G2 homodimer binds to leukocyte Ig-like receptor B2 with slow dissociation and a significant avidity effect. These findings provide novel insights into leukocyte Ig-like receptor B2-mediated immune regulation by the HLA-G2 isoform, as well as the gene evolution of HLA classes.

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Section: Hla-g2 Proteins Bind To Lilrb2 With a Notable Avidity Effectmentioning

confidence: 55%

Section: Hla-g2 Proteins Bind To Lilrb2 With a Notable Avidity Effectmentioning

confidence: 93%

mentioning

confidence: 98%

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Cutting Edge: Class II–like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

Kuroki

Mio

Takahashi

et al. 2017

The Journal of Immunology

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“…Notably, the amounts of HLA-G inversely correlate with the severity of autoimmune diseases [5,6,7]. We also demonstrated that the administration of the HLA-G molecule improved the symptoms of the collagen induced arthritis model mice and the atopic dermatitis model mice [8,9,10]. Furthermore, certain tumor cells also express HLA-G on the surface to suppress immune activation and escape immune surveillance [11,12].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms

Furukawa

Meguro

Yamazaki

et al. 2019

IJMS

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The human leucocyte antigen (HLA)-G, which consists of seven splice variants, is a tolerogenic immune checkpoint molecule. It plays an important role in the protection of the fetus from the maternal immune response by binding to inhibitory receptors, including leukocyte Ig-like receptors (LILRs). Recent studies have also revealed that HLA-G is involved in the progression of cancer cells and the protection from autoimmune diseases. In contrast to its well characterized isoform, HLA-G1, the binding activities of other major HLA-G isoforms, such as HLA-G2, toward available anti-HLA-G antibodies are only partially understood. Here, we investigate the binding specificities of anti-HLA-G antibodies by using surface plasmon resonance. MEM-G9 and G233 showed strong affinities to HLA-G1, with a nM range for their dissociation constants, but did not show affinities to HLA-G2. The disulfide-linker HLA-G1 dimer further exhibited significant avidity effects. On the other hand, 4H84 and MEM-G1, which can be used for the Western blotting of HLA-G isoforms, can bind to native HLA-G2, while MEM-G9 and G233 cannot. These results reveal that HLA-G2 has a partially intrinsically disordered structure. Furthermore, MEM-G1, but not 4H84, competes with the LILRB2 binding of HLA-G2. These results provide novel insight into the functional characterization of HLA-G isoforms and their detection systems.

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“…In humans, some researchers demonstrated that LILRB family genes could bind with MHC class I and β2m [21]. As predicted, GFP-linked LILRB1 and LILRB3 showed a strikingly different pattern of gene expression compared with GFP alone.…”

Section: Resultsmentioning

confidence: 68%

Chicken novel leukocyte immunoglobulin-like receptor subfamilies B1 and B3 are transcriptional regulators of major histocompatibility complex class I genes and signaling pathways

Truong

Hong

Lee

et al. 2019

Asian-Australas J Anim Sci

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Objective The inhibitory leukocyte immunoglobulin-like receptors (LILRBs) play an important role in innate immunity. The present study represents the first description of the cloning and structural and functional analysis of LILRB1 and LILRB3 isolated from two genetically disparate chicken lines. Methods Chicken LILRB1-3 genes were identified by bioinformatics approach. Expression studies were performed by transfection, quantitative polymerase chain reaction. Signal transduction was analyzed by western blots, immunoprecipitation and flow cytometric. Cytokine levels were determined by enzyme-linked immunosorbent assay. Results Amino acid homology and phylogenetic analyses showed that the homologies of LILRB1 and LILRB3 in the chicken line 6.3 to those proteins in the chicken line 7.2 ranged between 97%–99%, while homologies between chicken and mammal proteins ranged between 13%–19%, and 13%–69%, respectively. Our findings indicate that LILRB1 and LILRB3 subdivided into two groups based on the immunoreceptor tyrosine-based inhibitory motifs (ITIM) present in the transmembrane domain. Chicken line 6.3 has two ITIM motifs of the sequence LxYxxL and SxYxxV while line 7.2 has two ITIM motifs of the sequences LxYxxL and LxYxxV. These motifs bind to SHP-2 (protein tyrosine phosphatase, non-receptor type 11) that plays a regulatory role in immune functions. Moreover, our data indicate that LILRB1 and LILRB3 associated with and activated major histocompatibility complex (MHC) class I and β2-microglobulin and induced the expression of transporters associated with antigen processing, which are essential for MHC class I antigen presentation. This suggests that LILRB1 and LILRB3 are transcriptional regulators, modulating the expression of components in the MHC class I pathway and thereby regulating immune responses. Furthermore, LILRB1 and LILRB3 activated Janus kinase2/tyrosine kinase 2 ( JAK2/TYK2 ); signal transducer and activator of transcription1/3 ( STAT1/3 ), and suppressor of cytokine signaling 1 genes expressed in Macrophage (HD11) cells, which induced Th1, Th2, and Th17 cytokines. Conclusion These data indicate that LILRB1 and LILRB3 are innate immune receptors associated with SHP-2, MHC class I, β2-microglobulin, and they activate the Janus kinase/signal transducer and activator of transcription signaling pathway. Thus, our study provides novel insights into the regulation of immunity and immunopathology.

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The immunosuppressive effect of domain-deleted dimer of HLA-G2 isoform in collagen-induced arthritis mice

Abstract: 28HLA-G is involved in maternal-fetal immune tolerance and is reported to be a natural 29 tolerogenic molecule. Seven-spliced isoforms including dimeric and β2m-free forms 30 have been identified. The major isoform, HLA-G1 (and its soluble type HLA-G5), binds

Cited by 16 publications

References 23 publications

Cutting Edge: Class II–like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

Cutting Edge: Class II–like Structural Features and Strong Receptor Binding of the Nonclassical HLA-G2 Isoform Homodimer

Evaluation of the Reactivity and Receptor Competition of HLA-G Isoforms toward Available Antibodies: Implications of Structural Characteristics of HLA-G Isoforms

Chicken novel leukocyte immunoglobulin-like receptor subfamilies B1 and B3 are transcriptional regulators of major histocompatibility complex class I genes and signaling pathways

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