Novel MHC Class I Structures on Exosomes

Lynch, Sarah; Santos, Susana G.; Campbell, Elaine C.; Nimmo, Ailish; Botting, Catherine H.; Prescott, Alan R.; Antoniou, Antony N.; Powis, Simon J.

doi:10.4049/jimmunol.0900798

Cited by 72 publications

(95 citation statements)

References 50 publications

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“…1, LILRB1-Fc stained .221-B7, -B27, -A2, and -A3 cells, marginally interacting with .221-B35 and -B51, irrespective of their HLA-I surface levels. This binding pattern appeared related with the expression of alleles containing cytoplasmic Cys residues, reported to promote HLA-I dimerization in exosomes [20,24]. Dimer formation, directly confirmed by western blotting, was associated with HLA-I molecules containing Cys 339 (i.e.…”

Section: Lilrb1 Preferentially Interacts With Classical Hla-i Moleculmentioning

confidence: 86%

“…To address whether such structural features might contribute to the LILRB1 interaction with classical HLA-I molecules, we analyzed with a soluble LILRB1-Fc fusion protein a panel of different HLA-I alleles transfected in the 721.221 cell line. As shown in expression of alleles containing cytoplasmic Cys residues, reported to promote HLA-I dimerization in exosomes [20,24]. Dimer formation, directly confirmed by western blotting, was associated with HLA-I molecules containing Cys 339 (i.e.…”

mentioning

confidence: 94%

“…On the other hand, cytoplasmic Cys residues were shown to be crucial for LILRB1 interaction with classical HLA-I molecules (e.g. HLA-B7) and their dimerization in exosomes [19][20][21]. To address whether such structural features might contribute to the LILRB1 interaction with classical HLA-I molecules, we analyzed with a soluble LILRB1-Fc fusion protein a panel of different HLA-I alleles transfected in the 721.221 cell line.…”

Section: Lilrb1 Preferentially Interacts With Classical Hla-i Moleculmentioning

confidence: 99%

“…HLA-B7 cytoplasmic Cys residues were shown to play a crucial role in LILRB1 recognition [19]; moreover, Cys325 and Cys339 were reported to be respectively involved in the formation of β2m-associated HLA-B27 and -A2 dimers in exosomes [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…In this context, HLA-G displays a unique Cys42 residue, allowing the formation of disulphide-linked dimers, which were shown to establish a high-affinity interaction with LILRB1 [15][16][17]. HLA-B27 β2m-free heavy chains (FHC) dimerizing through Cys67, efficiently interacted with LILRB2 [18].HLA-B7 cytoplasmic Cys residues were shown to play a crucial role in LILRB1 recognition [19]; moreover, Cys325 and Cys339 were reported to be respectively involved in the formation of β2m-associated HLA-B27 and -A2 dimers in exosomes [20,21].Altogether, these observations suggest that these noncanonical HLA class Ia conformers might enhance the interaction with LILRB1. In the present study experimental evidence supporting this hypothesis is provided.…”

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confidence: 99%

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Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers

et al. 2016

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Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1) has been reported to interact with a wide spectrum of HLA class I (HLA-I) molecules, albeit with different affinities determined by allelic polymorphisms and conformational features. HLA-G dimerization and the presence of intracellular Cys residues in HLA-B7 have been shown to be critical for their recognition by LILRB1. We hypothesized that dimerization of classical HLA class Ia molecules, previously detected in exosomes, might enhance their interaction with LILRB1. A soluble LILRB1-Fc fusion protein and a sensitive cellular reporter system expressing a LILRB1-ζ chimera were employed to assess receptor interaction with different HLA class Ia molecules transfected in the human lymphoblastoid 721.221 cell line. Under these conditions, intracellular Cys residues and HLA-I dimerization appeared associated with increased LILRB1 recognition. On the other hand, a marginal interaction of LILRB1 with primary monocytic cells, irrespective of their high HLA-I expression, was enhanced by type I interferon (IFN). This effect appeared disproportionate to the cytokineinduced increase of surface HLA-I expression and was accompanied by detection of HLA class Ia dimers. Altogether, the results support that a regulated assembly of these noncanonical HLA-I conformers during the immune response may enhance the avidity of their interaction with LILRB1.Keywords: HLA class I dimers r LILRB1 r Macrophages r Type-I interferon Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), also termed ILT2, LIR-1 or CD85j, is an inhibitory receptor expressed by different leukocyte lineages which specifically interacts with HLA class I (HLA-I) molecules and the UL18 human cytomegalovirus glycoprotein [1,2]. Monocytic cells display higher cell surface levels of LILRB1 than lymphocytes, Correspondence: Miguel López-Botet e-mail: miguel.lopez-botet@upf.edu reflecting the involvement of different promoters in transcriptional regulation [3].LILRB1 comprises an extracellular region with four Iglike domains (D1-D4) and a cytoplasmic tail containing four immunoreceptor tyrosine-based inhibition motifs (ITIM) which recruit the SHP-1 tyrosine phosphatase [1,2]. Similarly to the role of other HLA-I inhibitory receptors in NK and T cells, LILRB1 contributes to control leukocyte activation and differentiation. * These authors contributed equally to this work. * * These authors contributed equally to this work as senior co-authors. LILRB1 engagement was reported to inhibit NK cell-mediated cytotoxicity and cytokine production [1,4,5] as well as TCR-and BCR-triggered responses [1,6,7]. In monocytes, co-engagement of LILRB1 with CD64 prevented tyrosine phosphorylation of the FcεR-I γ chain adaptor and intracellular Ca 2+ mobilization [8]. LILRB1 modulated monocyte-derived dendritic cell differentiation and suppressed in vitro osteoclast development induc...

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Section: Lilrb1 Preferentially Interacts With Classical Hla-i Moleculmentioning

confidence: 86%

mentioning

confidence: 94%

Section: Lilrb1 Preferentially Interacts With Classical Hla-i Moleculmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers

et al. 2016

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Extracellular Vesicle Preparation and Analysis: A State‐of‐the‐Art Review

Wang,

Zhou,

Kong

et al. 2024

Advanced Science

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In recent decades, research on Extracellular Vesicles (EVs) has gained prominence in the life sciences due to their critical roles in both health and disease states, offering promising applications in disease diagnosis, drug delivery, and therapy. However, their inherent heterogeneity and complex origins pose significant challenges to their preparation, analysis, and subsequent clinical application. This review is structured to provide an overview of the biogenesis, composition, and various sources of EVs, thereby laying the groundwork for a detailed discussion of contemporary techniques for their preparation and analysis. Particular focus is given to state‐of‐the‐art technologies that employ both microfluidic and non‐microfluidic platforms for EV processing. Furthermore, this discourse extends into innovative approaches that incorporate artificial intelligence and cutting‐edge electrochemical sensors, with a particular emphasis on single EV analysis. This review proposes current challenges and outlines prospective avenues for future research. The objective is to motivate researchers to innovate and expand methods for the preparation and analysis of EVs, fully unlocking their biomedical potential.

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HLA–B27 Subtype Oligomerization and Intracellular Accumulation Patterns Correlate With Predisposition to Spondyloarthritis

Jeanty

Sourisce

Noteuil

et al. 2014

Arthritis & Rheumatology

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Objective. Mechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA-B27 remain poorly understood. SpA-like disease develops spontaneously in B*2705-transgenic rats, in conjunction with high HLA-B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA-B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution.Methods. HeLa cells were transfected with complementary DNA encoding for HLA-B proteins fused to yellow fluorescent protein and/or Renilla luciferase and harvested at an early phase and a later phase of expression. We monitored HLA-B intracellular trafficking and localization by means of microscopy and livecell imaging. Bioluminescence resonance energy transfer (BRET) and Western blotting were used to monitor HLA-B oligomerization.Results. At low expression levels, BRET signals were similarly elevated for all SpA-associated HLA-B27 alleles tested, but were lower for the nonassociated B*2706. Of note, at higher expression levels, HLA-B27 signals remained steady while signal for HLA-B7 decreased sharply, reaching the level observed for B*2706. This was due at least in part to a decreased oligomer proportion without unfolded protein response outbreak. Such differential behavior was not abrogated by proteasome inhibition. With increased expression, all HLA-B proteins accumulated to a high density in cytoplasmic vesicles with labile form and size. The extent of this phenomenon was closely correlated with the level of association with predisposition to SpA.Conclusion. To our knowledge, this is the first report of a correlation between the level of predisposition to SpA conferred by HLA-B27 alleles and their biochemical behavior. These findings open new perspectives for understanding the pathogenicity of HLA-B27.The class I major histocompatibility complex (MHC) molecule HLA-B27 is strongly associated with ankylosing spondylitis (AS) and other forms of spondyloarthritis (SpA), a group of related inflammatory rheumatic diseases characterized by axial and peripheral joint inflammation, sometimes with concomitant extraarticular manifestations including uveitis, psoriasis, and inflammatory bowel disease. Although this association was demonstrated 40 years ago (1,2) and has been extensively studied since then, its molecular basis remains largely unknown.

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Novel MHC Class I Structures on Exosomes

Cited by 72 publications

References 50 publications

Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers

Interaction of the LILRB1 inhibitory receptor with HLA class Ia dimers

Extracellular Vesicle Preparation and Analysis: A State‐of‐the‐Art Review

HLA–B27 Subtype Oligomerization and Intracellular Accumulation Patterns Correlate With Predisposition to Spondyloarthritis

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