Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide – MHC class I complexes

Thirdborough, Stephen M.; Roddick, Joanne S.; Radcliffe, Joanna N.; Howarth, Mark; Stevenson, Freda K.; Elliott, Tim

doi:10.1002/eji.200737832

Cited by 21 publications

(33 citation statements)

References 25 publications

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“…Another parameter that might characterize peptide HLA-I complexes involving SYFPEITHI peptides is peptide-HLA-I stability, which has been suggested to be a better indicator of peptide immunogenicity than affinity (19,20). Thus, we speculated whether Tpn 1-87 would affect the stability of peptide-HLA-I complexes and whether the Tpn 1-87 facilitation would depend upon the peptide-HLA-I stability.…”

Section: Resultsmentioning

confidence: 99%

“…However, findings from several different experimental systems suggest that tapasin selectively associates with peptide-receptive MHC-I molecules: 1) a direct interaction between recombinant tapasin and peptideempty HLA-A*02:01 was demonstrated, and this interaction was sensitive to and could be disrupted by MHC-I binding peptide (29); 2) when using purified microsomes, the addition of high affinity peptides efficiently released MHC-I from tapasin (30); 3) in the absence of suitable peptides, i.e. in the TAPdeficient T2 cells, MHC-I molecules accumulate bound to tapasin for over 40 min before dissociation (6, 30); 4) another study using recombinant tapasin and HLA-B*08:01 showed that tapasin acts directly on HLA-B*08:01 as a chaperone increasing the number of peptide-receptive MHC-I molecules (31); and 5) finally, tapasin was demonstrated to increase the average affinity of the peptides to MHC-I presented at the cell surface (32) and to increase the stability of peptide-MHC-I complexes (20). Hence, inside the PLC, tapasin is thought to retain and keep MHC-I molecules in a peptide-receptive state until trimming of suboptimal peptides or replacement with optimal peptides allows the release of stable peptide-MHC-I complexes from the PLC (33).…”

Section: Discussionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

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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“…Still, if no higher affinity peptide is present, many peptides can become trapped in the binding groove and presented at the surface because their encounter complexes can convert to the stable form. Intriguingly, it was recently shown that only in the presence, but not in the absence, of tapasin, peptides are presented according to their kinetic stability [45]. This suggests that the sequence features of the peptide that bring about the CP Ã -CP conversion are not identical to those that determine high-affinity equilibrium binding.…”

mentioning

confidence: 99%

Tapasin edits peptides on MHC class I molecules by accelerating peptide exchange

et al. 2009

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The endoplasmic reticulum (ER) protein tapasin is essential for the loading of high-affinity peptides onto MHC class I molecules. It mediates peptide editing, i.e. the binding of peptides of successively higher affinity until class I molecules pass ER quality control and exit to the cell surface. The molecular mechanism of action of tapasin is unknown. We describe here the reconstitution of tapasin-mediated peptide editing on class I molecules in the lumen of microsomal membranes. We find that in a competitive situation between high-and low-affinity peptides, tapasin mediates the binding of the high-affinity peptide to class I by accelerating the dissociation of the peptide from an unstable intermediate of the binding reaction. IntroductionMHC class I molecules present antigenic peptides on the cell surface for surveillance by cytotoxic T lymphocytes. The peptides (usually 8-10 aa in length) are generated in the cytosol and transported into the endoplasmic reticulum (ER), where they bind to the newly synthesized class I heterodimer, which consists of the heavy chain (HC) and beta-2 microglobulin (b 2 m). For most class I allotypes, optimal peptide loading (prior to exit toward the cell surface) requires an interaction with the peptide loading complex (PLC), which consists of the peptide transporter TAP, the lectin chaperone calreticulin, the protein disulfide isomerases ERp57 and possibly PDI, and the class I-specific peptide loading factor, tapasin [1,2]. In the PLC, class I binds directly to tapasin [3]. This interaction is crucial for the loading of high-affinity peptides onto most (''tapasin-dependent'') class I allotypes, and thus for their expression at the cell surface. Tapasin-mediated peptide binding proceeds in an iterative manner such that low-affinity peptides that are bound initially are successively displaced by higher affinity ones. This optimization process is known as peptide editing [4].The structure of tapasin has recently been solved [5], but it is still unclear how it induces class I molecules to bind high-affinity peptides in the presence of an excess (estimated to be a 1000-fold, [6]) of low-affinity peptides. Its mechanism of action has been addressed in different experimental systems, which have yielded different and sometimes conflicting results. In cell-based assays, tapasin leads to the increased surface expression, thermostability, and persistence of class I-peptide complexes [4,[7][8][9], but some reports state that it does not influence the composition of the peptide pool bound to class I [10,11]. In assays that use whole cells, the peptide editing function of tapasin may be obscured by ER/Golgi quality control [12], a role of tapasin in the trafficking of class I to or from the Golgi apparatus (Springer et al., unpublished data) [13,14], class I loading by alternative pathways [2], and the metabolic stabilization of TAP by tapasin [3]. In search of the molecular mechanism of peptide editing, several groups have Ã These authors contributed equally to this work. 214therefore es...

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“…In the absence of Tapasin, MHC I molecules can be loaded with fast off-rate suboptimal peptides that can be lost before reaching the cell surface. 12,13 The low surface expression of MHC I molecules resulted in impaired positive and negative thymic T-cell selection, resulting in a reduction of CD8 þ T-cell number in the thymus and periphery, and reduced antigen presentation to T cells, resulting in poor in vivo CTL response to influenza virus. 14,15 HBcAg 18-27 epitope (HBcAg [18][19][20][21][22][23][24][25][26][27] ) is a widely accepted as a CTL epitope to stimulate CTL response to hepatitis B core antigen (HBcAg).…”

mentioning

confidence: 99%

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

Chen

Tang

Zhang

et al. 2014

Laboratory Investigation

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HBV-specific cytotoxic T-lymphocyte (CTL) activity has a very important role in hepatitis B virus clearance. Present studies suggest that Tapasin, a endoplasmic reticulum (ER) chaperone, stabilizes the peptide-receptive MHC I conformation, allowing peptide exchange and increasing more peptides to be translocated into the ER. We have previously testified that cytoplasmic transduction peptide (CTP)-HBcAg 18-27 -Tapasin fusion protein could enter cytoplasm of dendritic cells, and enhance T cells' response to generate specific CTLs efficiently in vitro. In the present study, we evaluated specific immune responses of CTP-HBcAg 18-27 -Tapasin fusion protein in HLA-A2 transgenic mice (H-2K b ) and anti-viral ability in HBV transgenic mice, and explored the mechanisms probably involved in. The studies showed that CTP-HBcAg 18-27 -Tapasin not only increased production of cytokine IFN-g and interleukin-2 (IL-2), compared with CTP-HBcAg 18-27 , HBcAg 18-27 -Tapasin, and PBS, but also significantly induced the higher percentages of IFN-g þ CD8 þ T cells and specific CTL responses in HLA-A2 transgenic mice. Moreover, enhancement of specific CTL activity induced by the fusion protein reduced HBV DNA and hepatitis B surface antigen (HBsAg) levels and decreased the expression of HBsAg and hepatitis B core antigen (HBcAg) in liver tissue of HBV transgenic mice. In addition, CTP-HBcAg 18-27 -Tapasin could upregulate the expression of JAK2, Tyk2, STAT1, and STAT4 in T lymphocytes in HLA-A2 transgenic mice splenocytes. However, there was no significant difference on the expressions of JAK1, JAK3, and STAT6 between each group. In conclusion, CTP-HBcAg 18-27 -Tapasin fusion protein could enhance not only the percentages of CTLs but also induce robust specific CTL activity and inhibits hepatitis B virus replication in vivo, which was associated with activation of the JAK/STAT signaling pathway. Hepatitis B virus (HBV) infection remains a global problem, despite the effectiveness of the HBV vaccines in preventing infection. Although the factors that contribute to the clearance of the virus in acute self-limiting HBV infection or to the persistence of the virus in chronic HBV infection are not completely clear, increasing evidence suggests that host immune responses are an important factor in determining the outcome of HBV infection. 1,2 Acute individuals develop a strong, polyclonal, multispecific cytotoxic T-lymphocyte (CTL) response and a polyclonal T helper (Th) cell response to the virus typically, while these responses are markedly attenuated in chronically infected patients. 3,4 Persistent HBV infection is characterized by a weak adaptive immune response, thought to be due to inefficient CD4 þ T-cell priming in the early stage of virus infection and subsequent development of a quantitatively and qualitatively ineffective CD8 þ T-cell response. Studies of HBV infection in woodchucks and chimpanzees, as well as patients, are suggesting that multiple and frequent administration of the vaccine may be advisable in treatment of chronic...

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Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide – MHC class I complexes

Cited by 21 publications

References 25 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

Tapasin edits peptides on MHC class I molecules by accelerating peptide exchange

Tapasin modification on the intracellular epitope HBcAg18–27 enhances HBV-specific CTL immune response and inhibits hepatitis B virus replication in vivo

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