The origin and fate of β2m-free MHC class I molecules induced on activated T cells

Demaria, Sandra; Schwab, R; Bushkin, Yuri

doi:10.1016/0008-8749(92)90272-q

Cited by 61 publications

(75 citation statements)

References 29 publications

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“…Consequently, LILRmediated recognition of FHC could represent a novel mechanism of immune regulation by detection of altered conformation of HLA class I complexes. Increased cell surface expression of FHC is associated with the activation of lymphocytes (41)(42)(43)(44)(45)(46)(47) and potentially APCs (73). HLA-C is particularly prone to forming FHC due to its unusual stability in the absence of b 2 m (54,(74)(75)(76)(77), and this form of HLA-C is specifically upregulated during macrophage differentiation (78).…”

Section: Discussionmentioning

confidence: 99%

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HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

Jones

Kosmoliaptsis

Apps

et al. 2011

The Journal of Immunology

112

143

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Leukocyte Ig-like receptors (LILRs) are a family of innate immune receptors predominantly expressed by myeloid cells that can alter the Ag presentation properties of macrophages and dendritic cells. Several LILRs bind HLA class I. Altered LILR recognition due to HLA allelic variation could be a contributing factor in disease. We comprehensively assessed LILR binding to >90 HLA class I alleles. The inhibitory receptors LILRB1 and LILRB2 varied in their level of binding to different HLA alleles, correlating in some cases with specific amino acid motifs. LILRB2 displayed the weakest binding to HLA-B*2705, an allele genetically associated with several autoimmune conditions and delayed progression of HIV infection. We also assessed the effect of HLA class I conformation on LILR binding. LILRB1 exclusively bound folded β2-microglobulin–associated class I, whereas LILRB2 bound both folded and free H chain forms. In contrast, the activating receptor LILRA1 and the soluble LILRA3 protein displayed a preference for binding to HLA-C free H chain. To our knowledge, this is the first study to identify the ligand of LILRA3. These findings support the hypothesis that LILR-mediated detection of unfolded versus folded MHC modulates immune responses during infection or inflammation.

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Section: Discussionmentioning

confidence: 99%

“…Unfolded HLA class I molecules are a feature of activated lymphocytes (41)(42)(43)(44)(45)(46)(47) and their recognition and functions are of growing interest (45,48). The inhibitory receptor LILRB2 can bind to b 2 m-free forms of both the HLA-B27 allele as well as the nonclassical HLA-G molecule (20,23).…”

mentioning

confidence: 99%

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

Jones

Kosmoliaptsis

Apps

et al. 2011

The Journal of Immunology

112

143

View full text Add to dashboard Cite

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“…For example, the HLA-G FHC may bind the LIR-2 (ILT4) receptor similar to HLA-B27 FHC. One may assume a possible scenario in which the balance between the expression of MHC class I molecules (HLA-C, -E, and -G) present on EVT cells as FHC or as conformed proteins (24,58) would determine the strength of the inhibitory response. These FHCs following dissociation from ␤ 2 m are released from the cell surface through proteolytic cleavage by metalloproteases (24,58).…”

Section: Discussionmentioning

confidence: 99%

“…One may assume a possible scenario in which the balance between the expression of MHC class I molecules (HLA-C, -E, and -G) present on EVT cells as FHC or as conformed proteins (24,58) would determine the strength of the inhibitory response. These FHCs following dissociation from ␤ 2 m are released from the cell surface through proteolytic cleavage by metalloproteases (24,58). For example, in various pathological conditions, such as advanced HIV-1 infection or chronic hepatitis C, serum levels of ␤ 2 m-free HLA proteins are increased (59).…”

Section: Discussionmentioning

confidence: 99%

The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and β2-Microglobulin-Free HLA-G Molecules

Gonen‐Gross¹,

Achdout²,

Arnon³

et al. 2005

The Journal of Immunology

109

124

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For a proper development of the placenta, maternal NK cells should not attack the fetal extravillous cytotrophoblast cells. This inhibition of maternal NK cells is partially mediated via the nonclassical MHC class I molecule HLA-G. Recently, we demonstrated that HLA-G forms disulfide-linked high molecular complexes on the surface of transfected cells. In the present study, we demonstrate that HLA-G must associate with β2m for its interaction with CD85J/leukocyte Ig-like receptor-1 (LIR-1). Although HLA-G free H chain complexes are expressed on the surface, they are not recognized and possibly interfere with CD85J/LIR-1 and HLA-G interaction. The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition. We also show that endogenous HLA-G complexes are expressed on the cell surface. These findings provide novel insights into the delicate interaction between extravillous cytotrophoblast cells and NK cells in the decidua.

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“…Interestingly, cell surface expression of g 2 mfree class I heavy chains has previously been described for several cell types, including activated and resting T cells [30][31][32], EBV-transformed B cell lines [33,34], and spleen cells from HLA-B27/human g 2 m transgenic mice [8]. However, these studies did not look for evidence of homodimerization.…”

Section: Discussionmentioning

confidence: 99%

Lymphoblastoid cells express HLA‐B27 homodimers both intracellularly and at the cell surface following endosomal recycling

et al. 2003

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The MHC class I allele HLA-B27 is very strongly associated with development of autoimmune spondyloarthritis, although the disease mechanism remains unknown. Class I molecules classically associate in the endoplasmic reticulum (ER) with g 2-microglobulin ( g 2 m) and antigenic peptides for cell surface expression and presentation to T cells. We have previously shown that HLA-B27 is capable of forming g 2 m-free disulfide-bonded homodimers in vitro. Here we show that HLA-B27 forms disulfide-bonded homodimers in vivo by two distinct pathways. HLA-B27 homodimers form in the ER but appear unable to egress to the cell surface in human cells. Cell surface HLA-B27 homodimers are abundantly expressed in a variety of lymphoid cell lines. Experiments with inhibitors indicate that HLA-B27 homodimers can arise from cell-surface heterodimers via an endosome-dependent recycling pathway. HLA-B27 homodimer expression on the cell surface of 721.220 is dependent on the unpaired cysteine 67 and is inhibited by restoration of tapasin function or by incubation with peptides that bind strongly to HLA-B27 heterodimers. Cell surface expressed HLA-B27 homodimers are likely to be immunologically reactive ligands for NK family immunoreceptors and, hence, could play a pathogenic role in spondyloarthritis.

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The origin and fate of β2m-free MHC class I molecules induced on activated T cells

Cited by 61 publications

References 29 publications

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and β2-Microglobulin-Free HLA-G Molecules

Lymphoblastoid cells express HLA‐B27 homodimers both intracellularly and at the cell surface following endosomal recycling

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