Structural basis for a major histocompatibility complex class Ib–restricted T cell response

Hoare, Hilary Linda; Sullivan, Lucy C.; Pietra, Gabriella; Clements, Craig Steven; Lee, Eleanor J; Ely, Lauren Kate; Beddoe, Travis; Falco, Michela; Reid, Hugh H.; McCluskey, James; Moretta, Alessandro; Rossjohn, Jamie; Brööks, Andrëw G.

doi:10.1038/ni1312

Cited by 105 publications

(138 citation statements)

References 54 publications

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“…The Qa-1 b H chain and murine b 2 -microglobulin were expressed separately in Escherichia coli, refolded, and purified, essentially as described previously (33,34). Following reverse transcription of RNA prepared from C57BL/6 splenocytes, cDNAs encoding residues 43-179 and 119-224 of CD94 and NKG2A, respectively, were generated by PCR and cloned into a pET-30-based vector.…”

Section: Methodsmentioning

confidence: 99%

“…Crystals of the refolded Qa-1 b-AMAPRTLLL complex formed in the space group P2 1 2 1 2 1 with unit cell dimensions of a = 59.3, b = 72.8, and c = 95.8 Å , and diffracted to a resolution of 1.9 Å . The asymmetric unit comprised one heterodimer, and the structure was solved by molecular replacement using HLA-E as the search probe (34). The Qa-1 b-AMAPRTLLL structure was subsequently refined to R factor and R free values of 19.5 and 24.9%, respectively.…”

Section: Structural Overview Of Qa-1 Bmentioning

confidence: 99%

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A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

Sullivan

Vivian

et al. 2012

The Journal of Immunology

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The primary function of the monomorphic MHC class Ib molecule Qa-1b is to present peptides derived from the leader sequences of other MHC class I molecules for recognition by the CD94-NKG2 receptors expressed by NK and T cells. Whereas the mode of peptide presentation by its ortholog HLA-E, and subsequent recognition by CD94-NKG2A, is known, the molecular basis of Qa-1b function is unclear. We have assessed the interaction between Qa-1b and CD94-NKG2A and shown that they interact with an affinity of 17 μM. Furthermore, we have determined the structure of Qa-1b bound to the leader sequence peptide, Qdm (AMAPRTLLL), to a resolution of 1.9 Å and compared it with that of HLA-E. The crystal structure provided a basis for understanding the restricted peptide repertoire of Qa-1b. Whereas the Qa-1b-AMAPRTLLL complex was similar to that of HLA-E, significant sequence and structural differences were observed between the respective Ag-binding clefts. However, the conformation of the Qdm peptide bound by Qa-1b was very similar to that of peptide bound to HLA-E. Although a number of conserved innate receptors can recognize heterologous ligands from other species, the structural differences between Qa-1b and HLA-E manifested in CD94-NKG2A ligand recognition being species specific despite similarities in peptide sequence and conformation. Collectively, our data illustrate the structural homology between Qa-1b and HLA-E and provide a structural basis for understanding peptide repertoire selection and the specificity of the interaction of Qa-1b with CD94-NKG2 receptors.

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Section: Methodsmentioning

confidence: 99%

Section: Structural Overview Of Qa-1 Bmentioning

confidence: 99%

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

Sullivan

Vivian

et al. 2012

The Journal of Immunology

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“…All of the PWHA with KS studied here tested positive for CMV immunoglobulin G (data not shown), indicating that CMV status is not the sole determining factor in driving NKG2C ϩ cells in these patients. It will be interesting to assess whether HLA-E and classical HLA-A and -B alleles, which influence NK and T-cell responses to CMV, also influence disease stage in KS patients (12). It therefore may be that disease outcome in AIDS KS patients is influenced indirectly by infections other than KSHV which influence immune competence.…”

mentioning

confidence: 99%

NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

Goodier

Mela

Steel³

et al. 2007

J Virol

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Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals withRecognition of infected target cells by NK cells is regulated by receptors for major histocompatibility complex class I (MHC-I) and pathogen-derived molecules (3,14). Killer cell immunoglobulin-like receptor (KIR) family members, which are expressed on NK cells, influence the risk of progression to AIDS in combination with HLA-B alleles (15, 16). However, the proportion of NK cells expressing inhibitory KIR increases and those expressing activating natural cytotoxicity receptors (NCR) are less abundant in PWHA (1,5,6,17).We have shown that NK cells from PWHA are enriched for a subset bearing the C-type, lectin-like receptor NKG2C (20). The NKG2C receptor mediates NK cell responses to a limited set of ligands in association with HLA-E, including a human cytomegalovirus (HCMV) peptide, and to HCMV-infected fibroblasts (9, 10). However, NK cells bearing NKG2C predominantly express inhibitory KIR and have low levels of activating NCR, which may compromise their abilities to mount cytolytic responses (8,20).As NKG2C ϩ NK cells have a predominantly inhibitory phenotype, the dominance of this subset could have an impact on disease prognosis in AIDS patients, including those with KS. We used the AIDS Clinical Trial Group (ACTG) clinical staging system, which is applied to all AIDS KS patients upon diagnosis, to investigate the relationship between the NK cell phenotype and function and disease prognosis in HIV-1 infection.Patients

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“…The TCR interacts with four unique amino acids in the HLA-E molecule and the interaction between the TCR and HLA-E is of low affinity. 74 …”

Section: Mhc-peptide Interaction With the Tcrmentioning

confidence: 99%

“…4). 74 The CDR2 b uses 30% of the buried surface area at the interface and all three CDR b loops interact with residue 8 of the bound peptide, indicating that this residue determines self from nonself peptides. The TCR interacts with four unique amino acids in the HLA-E molecule and the interaction between the TCR and HLA-E is of low affinity.…”

Section: Mhc-peptide Interaction With the Tcrmentioning

confidence: 99%

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

Apostolopoulos¹,

Yuriev²,

Lazoura³

et al. 2008

Human Vaccines

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© 2 0 0 8 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .peptide-binding proteins as well as antigen processing molecules, such as TAP and tapasin. The MHC class II locus encodes heterodimeric peptide-binding proteins and proteins that modulate peptide loading onto MHC class II proteins in the lysosomal compartment, such as MHC class II DM, -DQ and -DP. MHC class I proteins are expressed on all nucleated cells and MHC class II are found on only a few specialized cell types; B-cells, neutrophils, dendritic cells and thymic epithelial cells and can be induced on macrophages and human T cells. The MHC class III locus encodes for other immune components, i.e., complement components (C2, C4, factor B), cytokines (TNFα and TNFb) and HSP70. Stimulation of CD8 T CellsMHC, first described more than 70 years ago to control transplant rejection in mice, was initially termed H-2. There are three gene families for murine MHC class I: H-2K, H-2D and H-2L and for human MHC: HLA-A, HLA-B and HLA-C. The first step in CD8 + T cell generation is the uptake and presentation of peptides by antigen presenting cells through their MHC molecules. Peptides bound to MHC class I are usually endogenous and cytosolic although exogenous peptides may also be presented by MHC class I molecules. 4,5 Exogenous antigens are taken up by antigen presenting cells (APCs), primarily dendritic cells, into phagosomes and early and late endosomes and presented to MHC class II molecules. Numerous reports have demonstrated that in early endosomes some antigens can either degrade or escape out of the endosome into the cytosol and enter the proteasome. 4,5 Likewise, endogenous peptides are primarily generated in the cytosol by the proteasome. From this point, exogenous-and endogenous-derived peptides follow the same pathway. The proteasome consists of 24 subunits, half of which contain proteolytic activity. The proteasome degrades antigens (proteins) into small peptides which are released into the cytosol. The peptides are transported from the cytosol into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP1 and TAP2) by ATP. In the ER, peptides bind to the newly synthesized MHC class I molecules following the formation of a large multimeric complex which involves TAP, tapasin, calreticulin, calnexin and ER60. From the ER, the peptide-MHC class I complex is transported to the surface of APCs through the secretory pathway (Golgi) where the complex undergoes several posttranslational modifications. Then the peptide-MHC class I complexes expressed

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Structural basis for a major histocompatibility complex class Ib–restricted T cell response

Cited by 105 publications

References 54 publications

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

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Structural basis for a major histocompatibility complex class Ib–restricted T cell response

Cited by 105 publications

References 54 publications

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

NKG2C + NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

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Product

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NKG2C ⁺ NK Cells Are Enriched in AIDS Patients with Advanced-Stage Kaposi's Sarcoma