Open conformers: the hidden face of MHC-I molecules

Arosa, Fernando A.; Santos, Susana G.; Powis, Simon J.

doi:10.1016/j.it.2007.01.002

Cited by 98 publications

(160 citation statements)

References 97 publications

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“…This view is consistent with recently reviewed experimental data (Arosa et al, 2007) showing that '...HLA open conformers adopt a supine orientation with the long heavy chain axis parallel to the plasma membrane (like HFE and M10) (Mitra et al, 2004), in a position that favours cis interactions between the a1 and a2 domains and adjacent receptors'. In addition, some NK receptors recognize peptide-empty MHC molecules (HLA-G and H-2K b ; Benoit et al, 2005;Gonen-Gross et al, 2005), thus supporting the view that open MHC-I conformers can serve as cis-trans recognition structures.…”

Section: Discussionsupporting

confidence: 91%

“…2c, d). This view is consistent with recently reviewed experimental data (Arosa et al, 2007) siRNA design and transfection protocols. The HLA-C-specific siRNAs used were J-017513-06 and J-017513-08 (Dharmacon; Matucci et al, 2008) for the experiments with TZM-bl cells; only the latter was used in the experiments with PBLs.…”

supporting

confidence: 91%

“…molecules devoid of peptide with or without b 2 -microglobulin). As recently reviewed elsewhere (Arosa et al, 2007), open conformers of MHC molecules are involved in homotypic and heterotypic cis and trans interactions with other surface proteins. This notion is probably the key to understanding how HLA-C could affect HIV-1 entry from both sides of the interaction (virion and cellular).…”

Section: Discussionmentioning

confidence: 95%

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HLA-C is necessary for optimal human immunodeficiency virus type 1 infection of human peripheral blood CD4 lymphocytes

Baroni

Matucci

Scarlatti

et al. 2009

Journal of General Virology

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The hypothesis that open conformers of HLA-C on target cells might directly exert an effect on their infectability by human immunodeficiency virus (HIV) has been suggested previously. This was tested by exploiting the peculiar specificity of monoclonal antibody (mAb) L31 for HLA-C open conformers to show that normal levels of Env-driven fusion were restored in HLA-C transfectants of a major histocompatibility complex-deleted (fusion-incompetent) cell line. The physiological relevance of this finding is now confirmed in this report, where small interfering RNA (siRNA) technology was used to silence HLA-C expression in peripheral blood lymphocytes (PBLs) from 11 healthy donors. Infectability by HIV (strains IIIB and Bal and primary isolates) was significantly reduced (P50.016) in silenced cells compared with cells that maintained HLA-C expression in 10 of the 11 PBL donors. Normal infectability was resumed, together with HLA-C expression, when the effect of siRNA interference waned after several days in culture. Additional confirmation of the HLA-C effect was obtained in several assays employing HLA-C-positive and -negative cell lines, a number of HIV strains and also pseudoviruses. In particular, viruses pseudotyped with env genes from HIV strains AC10 and QH0692.42 were assayed on siRNA-silenced lymphocytes from three healthy donors: the differences in infection with pseudoviruses were even higher than those observed in infections with normal viruses. INTRODUCTIONThree recent whole-genome association studies have demonstrated and confirmed that minor allele variants of singlenucleotide polymorphisms in the major histocompatibility complex (MHC; in particular HLA-C) gene regions are associated with a lower viral load at the set point and additionally with delayed human immunodeficiency virus type 1 (HIV-1) disease progression (Fellay et al., 2007;Limou et al., 2009;van Manen et al., 2009). These findings, which echo a previous report on the association between HLA-C alleles and rapid progression to AIDS (Carrington et al., 1999), have prompted wide speculations on the role of HLA (and HLA-C in particular) in HIV biology and immunology. HLA-C differs from HLA-A and -B because HIV-1 selectively downregulates HLA-A and -B, but does not significantly affect HLA-C (or HLA-E). Therefore, infected cells display reduced detection by both cytotoxic lymphocytes and natural killer (NK) cells (Cohen et al., 1999). The hypothesis that HLA-C might exert an effect directly on HIV infectivity was originally suggested by De Santis et al. (1996), exploiting the peculiar specificity of monoclonal antibody (mAb) L31 to show that normal levels of Env-driven fusion were restored in HLA-C transfectants (Grassi et al., 1991;Setini et al., 1996) of an MHC-deleted (fusion-incompetent) cell line. The physiological relevance of this finding is confirmed in this report, where small interfering RNA (siRNA) technology was used to silence HLA-C expression in peripheral blood lymphocytes (PBLs), the natural target of HIV-1. Two different kinds o...

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Section: Discussionsupporting

confidence: 91%

supporting

confidence: 91%

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

HLA-C is necessary for optimal human immunodeficiency virus type 1 infection of human peripheral blood CD4 lymphocytes

Baroni

Matucci

Scarlatti

et al. 2009

Journal of General Virology

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“…This is a supramolecular endoplasmic reticulum structure comprising, among others, two HLA-dedicated chaperones: TAP transporter associated with antigen processing) and the peptide editor/facilitator tapasin (1). Successful peptide loading results in tight association of the heavy chain with ␤ 2 m and the release of thermally stable, folded class I conformers (1)(2)(3). These are exported to the cell surface, where they activate and inhibit cytotoxic T lymphocytes expressing the rearranging T cell receptor and natural killer (NK) cells expressing non-rearranging receptors such as the killer immunoglobulin-like receptors, respectively (4).…”

mentioning

confidence: 99%

A Single Bottleneck in HLA-C Assembly

Sibilio¹,

Martayan²,

Setini³

et al. 2008

Journal of Biological Chemistry

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Poor assembly of class I major histocompatibility HLA-C heavy chains results in their intracellular accumulation in two forms: free of and associated with their light chain subunit (␤ 2 -microglobulin). Both intermediates are retained in the endoplasmic reticulum by promiscuous and HLA-dedicated chaperones and are poorly associated with peptide antigens. In this study, the eight serologically defined HLA-C alleles and the interlocus recombinant HLA-B46 allele (sharing the HLA-Cspecific motif KYRV at residues 66 -76 of the ␣1-domain ␣-helix) were compared with a large series of HLA-B and HLA-A alleles. Pulse-labeling experiments with HLA-C transfectants and HLA homozygous cell lines demonstrated that KYRV alleles accumulate as free heavy chains because of both poor assembly and post-assembly instability. Reactivity with antibodies to mapped linear epitopes, co-immunoprecipitation experiments, and molecular dynamics simulation studies additionally showed that the KYRV motif confers association to the HLA-dedicated chaperones TAP and tapasin as well as reduced plasticity and unfolding in the peptide-binding groove. Finally, in vitro assembly experiments in cell extracts of the T2 and 721.220 mutant cell lines demonstrated that HLA-Cw1 retains the ability to form a peptide-receptive interface despite a lack of TAP and functional tapasin, respectively. In the context of the available literature, these results indicate that a single locusspecific biosynthetic bottleneck renders HLA-C peptide-selective (rather than peptide-unreceptive) and a preferential natural killer cell ligand.Class I human leukocyte antigens (called HLA) are cell-surface heterotrimers formed by a highly polymorphic heavy (44 kDa) chain, a non-polymorphic light (12 kDa) chain subunit (␤ 2 -microglobulin (␤ 2 m)3 ), and a short (8 -11-mer) peptide antigen derived from the degradation of intracellular proteins (1). The assembly pathway of most class I molecules involves an early interaction of the heavy chain, still free of ␤ 2 m, with calnexin, followed by association with ␤ 2 m and binding to the so-called peptide-loading complex. This is a supramolecular endoplasmic reticulum structure comprising, among others, two HLA-dedicated chaperones: TAP transporter associated with antigen processing) and the peptide editor/facilitator tapasin (1). Successful peptide loading results in tight association of the heavy chain with ␤ 2 m and the release of thermally stable, folded class I conformers (1-3). These are exported to the cell surface, where they activate and inhibit cytotoxic T lymphocytes expressing the rearranging T cell receptor and natural killer (NK) cells expressing non-rearranging receptors such as the killer immunoglobulin-like receptors, respectively (4).There are Ͼ1000 class I molecules, encoded by three highly polymorphic allelic series: HLA-A, -B, and -C (www. anthonynolan.org.UK/HIG/index.html). They share a conserved general architecture, a common peptide-loading pathway, and a similar set of functions, but also display a number of allel...

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“…They are not as polymorphic as the classical MHC class I and some of them do not require -2-microglobulin or the binding of peptide in order to reach the cell surface (Arosa et al 2007). Non-classical MHC class I are also implicated in a wide range of immune and nonimmune processes, from presentation of glycolipids to regulation of pheromone signalling (Arosa et al 2007, Fishman et al 2004.…”

mentioning

confidence: 99%

Immune Privilege Revisited: The Roles of Neuronal MHC Class I Molecules in Brain Development and Plasticity

Ribic¹

2012

Histocompatibility

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Open conformers: the hidden face of MHC-I molecules

Cited by 98 publications

References 97 publications

HLA-C is necessary for optimal human immunodeficiency virus type 1 infection of human peripheral blood CD4 lymphocytes

HLA-C is necessary for optimal human immunodeficiency virus type 1 infection of human peripheral blood CD4 lymphocytes

A Single Bottleneck in HLA-C Assembly

Immune Privilege Revisited: The Roles of Neuronal MHC Class I Molecules in Brain Development and Plasticity

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