Tapasin enhances MHC class I peptide presentation according to peptide half-life

Howarth, Mark; Williams, Anthony P.; Tolstrup, Anne B.; Elliott, Tim

doi:10.1073/pnas.0306294101

Cited by 164 publications

(173 citation statements)

References 45 publications

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“…Having analyzed the peptide repertoire presented by MHC-I on the cell surface, a previous study suggested that tapasin controls the peptide repertoire, resulting in the presentation of more stable peptide-MHC-I complexes (28). At first glance, our finding that the Tpn 1-87 facilitation was high for unstable peptide-HLA-A*02:01 complexes seems to contradict the suggested role of tapasin as a mediator of cell surface expression of stable peptide-HLA-I complexes.…”

Section: Discussionmentioning

confidence: 99%

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

Røder

Geironson

Rasmussen

et al. 2011

Journal of Biological Chemistry

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A plethora of peptides are generated intracellularly, and most peptide-human leukocyte antigen (HLA)-I interactions are of a transient, unproductive nature. Without a quality control mechanism, the HLA-I system would be stressed by futile attempts to present peptides not sufficient for the stable peptide-HLA-I complex formation required for long term presentation. Tapasin is thought to be central to this essential quality control, but the underlying mechanisms remain unknown. Here, we report that the N-terminal region of tapasin, Tpn 1-87 , assisted folding of peptide-HLA-A*02:01 complexes according to the identity of the peptide. The facilitation was also specific for the identity of the HLA-I heavy chain, where it correlated to established tapasin dependence hierarchies. Two large sets of HLA-A*02:01 binding peptides, one extracted from natural HLA-I ligands from the SYFPEITHI database and one consisting of medium to high affinity non-SYFPEITHI ligands, were studied in the context of HLA-A*02:01 binding and stability. We show that the SYFPEITHI peptides induced more stable HLA-A*02:01 molecules than the other ligands, although affinities were similar. Remarkably, Tpn 1-87 could functionally discriminate the selected SYFPEITHI peptides from the other peptide binders with high sensitivity and specificity. We suggest that this HLA-I-and peptide-specific function, together with the functions exerted by the more C-terminal parts of tapasin, are major features of tapasin-mediated HLA-I quality control. These findings are important for understanding the biogenesis of HLA-I molecules, the selection of presented T-cell epitopes, and the identification of immunogenic targets in both basic research and vaccine design.Mature HLA-I 3 molecules are located on the surface of all nucleated cells where they present peptides to CD8ϩ T lymphocytes. Before the peptide-HLA-I complex is transported to the cell surface, maturation and assembly with peptides occur in the ER. During late stage maturation, HLA-I molecules are integrated in the peptide-loading complex (PLC), which at least consists of TAP1/2, tapasin, calreticulin, protein disulfide isomerase, ERp57, and HLA-I (1, 2). Integration of HLA-I into the PLC is mediated by tapasin, which structurally bridges HLA-I and TAP (3, 4). Tapasin is a multi-domain protein, which has been suggested to perform multiple functions. Tapasin has been shown to enhance peptide binding to TAP, facilitate peptide loading onto HLA-I, edit the HLA-I bound peptide repertoire, and retain and recycle suboptimally loaded peptide-HLA-I complexes (5-9). Consequently, in the absence of tapasin, cell surface-expressed HLA-I molecules are less stable and present a partly different peptide repertoire than HLA-I on wild-type cells (10 -12). The effect of tapasin depends on the HLA-I allomorph where certain allomorphs, such as HLA-A*02:01, are dependent on tapasin for efficient presentation, whereas others are less influenced (10 -12).Recently, we showed that an N-terminal fragment of tapasin, Tpn 1-87 , assi...

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Section: Discussionmentioning

confidence: 99%

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

Røder

Geironson

Rasmussen

et al. 2011

Journal of Biological Chemistry

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“…Tapasin simultaneously binds to peptide-receptive MHC class I heterodimers and to TAP, localizing MHC class I to a concentrated source of newly degraded antigenic peptides (1)(2)(3)(4)(5). There is also evidence that tapasin optimizes or edits the peptides presented on MHC class I by facilitating exchange of suboptimal peptides for higher-affinity cargo (6)(7)(8)(9)(10).…”

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confidence: 99%

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

Hermann

Strittmatter

Deane

et al. 2013

The Journal of Immunology

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The loading of peptide antigens onto MHC class I molecules is a highly controlled process in which the MHC class I dedicated chaperone tapasin is a key player. We recently identified a tapasin related molecule, TAPBPR, as an additional component in the MHC class I antigen presentation pathway. Here we show that the amino acid residues important for tapasin to interact with MHC class I are highly conserved on TAPBPR. We identify specific residues in the N-terminal and C-terminal domains of TAPBPR involved in associating with MHC class I. Furthermore, we demonstrate that residues on MHC class I crucial for its association with tapasin, such as T134, are also essential for its interaction with TAPBPR. Taken together, the data indicate that TAPBPR and tapasin bind in a similar orientation to the same face of MHC class I. In the absence of tapasin, the association of MHC class I with TAPBPR is increased. However, in the absence of TAPBPR, the interaction between MHC class I and tapasin does not increase. In light of our findings, previous data determining the function of tapasin in the MHC class I antigen processing and presentation pathway must be re-evaluated.

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“…2A), that contains an altered OVA peptide ligand SIINYEKL, which binds to K b with a 1,000-fold lower affinity compared with the WT peptide Fig. S3) (16). To test whether this altered peptide from the SCT could be cross-presented, we immunized mice with DNA vaccines with the keratinocyte-specific K14 promoter (17) driving expression of cDNA or SCT constructs corresponding to either WT OVA or the mutant SIINYEKL sequence (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cross-dressed CD8α ⁺ /CD103 ⁺ dendritic cells prime CD8 ⁺ T cells following vaccination

Li¹,

Kim

Herndon³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Activation of naïve cluster of differentiation (CD)8 + cytotoxic T lymphocytes (CTLs) is a tightly regulated process, and specific dendritic cell (DC) subsets are typically required to activate naive CTLs. Potential pathways for antigen presentation leading to CD8 + T-cell priming include direct presentation, cross-presentation, and cross-dressing. To distinguish between these pathways, we designed single-chain trimer (SCT) peptide-MHC class I complexes that can be recognized as intact molecules but cannot deliver antigen to MHC through conventional antigen processing. We demonstrate that cross-dressing is a robust pathway of antigen presentation following vaccination, capable of efficiently activating both naïve and memory CD8 + T cells and requires CD8α + / CD103 + DCs. Significantly, immune responses induced exclusively by cross-dressing were as strong as those induced exclusively through cross-presentation. Thus, cross-dressing is an important pathway of antigen presentation, with important implications for the study of CD8 + T-cell responses to viral infection, tumors, and vaccines. P rofessional antigen-presenting cells (APCs) are typically required to activate naïve cluster of differentiation (CD)8 + T cells, either by direct priming or cross-priming. In direct priming, infected (viral infection) or directly transfected (DNA vaccination) APCs synthesize the foreign antigen and use endogenous MHC class I pathways of antigen presentation to present antigen and prime CD8 + T cells. In cross-priming, APCs are able to capture, process, and present exogenous antigen onto MHC class I molecules through a process known as cross-presentation (1). Cross-priming has been shown to be an essential pathway for immunity to many viral infections and tumors. Although the pathways that lead to cross-presentation remain incompletely understood, increasing evidence suggests that only certain dendritic cell (DC) subsets are efficient in this process.Cross-dressing involves the transfer of intact MHC class I/ peptide complexes between cells without the requirement for further processing, representing an alternative pathway of indirect antigen presentation (2, 3). Although cross-dressed DCs can activate memory CD8 + T cells following viral infection in vivo (4), it remains unclear whether cross-dressing can prime naïve CD8 + T-cell responses, what DC subtypes are required to prime CD8 + T cells by cross-dressing, and how robust this pathway is compared with traditional pathways of indirect antigen presentation. These questions must be addressed before the physiologic relevance of cross-dressing can be evaluated in context.To address these questions, we have taken advantage of Batf3-deficient mice and engineered MHC class I single chain trimer (SCT) constructs. Batf3 −/− mice have a selective loss of CD8α + and CD103 + DCs, without abnormalities in other hematopoietic cell types or architecture (5). DCs from Batf3 −/− mice are deficient in cross-presentation, and cytotoxic T lymphocyte (CTL) responses to viral infection and synge...

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Tapasin enhances MHC class I peptide presentation according to peptide half-life

Cited by 164 publications

References 45 publications

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

Cross-dressed CD8α ⁺ /CD103 ⁺ dendritic cells prime CD8 ⁺ T cells following vaccination

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Tapasin enhances MHC class I peptide presentation according to peptide half-life

Cited by 164 publications

References 45 publications

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

Tapasin Discriminates Peptide-Human Leukocyte Antigen-A*02:01 Complexes Formed with Natural Ligands

The Binding of TAPBPR and Tapasin to MHC Class I Is Mutually Exclusive

Cross-dressed CD8α + /CD103 + dendritic cells prime CD8 + T cells following vaccination

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Cross-dressed CD8α ⁺ /CD103 ⁺ dendritic cells prime CD8 ⁺ T cells following vaccination