A CTL epitope from human cytomegalovirus IE1 defined by combining prediction of HLA binding and proteasomal processing is the target of dominant immune responses in patients after allogeneic stem cell transplantation

Hebart, Holger; Rauser, Georg; Stevanović, Stefan; Haenle, Claire; Nussbaum, Alexander K.; Meisner, Christoph; Bissinger, Alfred Lennart; Tenzer, Stefan; Jahn, Gerhard; Loeffler, Juergen; Rammensee, Hans‐Georg; Schild, Hansjörg; Einsele, Hermann

doi:10.1016/s0301-472x(03)00203-0

Cited by 22 publications

(17 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To the best of our knowledge, there exists only one report addressing the question of a contribution of IE1-specific CD8 T cells to protection against human CMV disease. Specifically, as reported by Hebart et al (15) for a limited number of recipients of an allogeneic stem cell transplantation with hCMV reactivation prior to day 100, the median duration of hCMV-DNAemia in patients with reconstitution of IE1-specific and UL83/pp65-specific CD8 T cells was significantly shorter than in patients with reconstitution of UL83/pp65-specific CD8 T cells only.…”

Section: Discussionmentioning

confidence: 52%

Highly Protective In Vivo Function of Cytomegalovirus IE1 Epitope-Specific Memory CD8 T Cells Purified by T-Cell Receptor-Based Cell Sorting

Pahl-Seibert

Juelch

Podlech

et al. 2005

J Virol

105

View full text Add to dashboard Cite

Reconstitution of antiviral CD8 T cells is essential for controlling cytomegalovirus (CMV) infectionThe L d -restricted immediate-early 1 (IE1) peptide 168-YPHFMPTNL-176 of murine cytomegalovirus (mCMV) was the first antigenic peptide to be identified for a herpesvirus (50). The IE1 protein derived from open reading frame (ORF) m123, an intranuclear phosphoprotein which exists in molecular species of 89 and 76 kDa (32), is expressed in the IE phase of viral gene expression and performs regulatory and transactivating functions (12,31,39). It is encoded in transcription unit ie1/3 of which mRNAs specifying proteins IE1 (encoded by exons 2, 3, and 4) and IE3 (encoded by exons 2, 3, and 5) are generated by differential splicing (31, 39). The IE1 protein is processed to yield peptide 168-YPHFMPTNL-176 and an Nterminally elongated precursor 166-DMYPHFMPTNL-176 by the constitutive proteasome and, more efficiently, by the immunoproteasome, with only the precursor being translocated into the lumen of the endoplasmic reticulum for major histocompatibility complex class I (MHC-I) loading (36). N-terminal trimming finally leads to the IE1 peptide presented by the MHC-I molecule L d (reviewed in reference 45). Based on the frequency of IE1 epitope-specific CD8 T cells primed during acute infection and on the establishment of long-term IE1-specific memory, the IE1 peptide was classified as one of just two immunodominant MHC-I-restricted antigenic peptides in the H-2 d haplotype (25). Owing to MHC polymorphism, it is evident that immunodominance of peptides and the proteins from which they are derived cannot be extrapolated to other haplotypes in the same animal species. This is all the more true for extrapolation from mCMV to antigenic peptides of human cytomegalovirus (hCMV) presented by HLA molecules. Thus, although an early report by Borysiewicz et al. (4) had indicated the CD8 T-cell immunogenicity of the hCMV IE1 ortholog, the predictive value of the BALB/c mouse model in terms of the role of IE proteins in immunity to CMVs has been debated for a long time, until more recently the IE1 immunogenicity in humans was revisited with unbiased new methodology (10,14,33,34). Most intriguingly, in a comprehensive pangenomic search for antigenic ORFs of hCMV by using overlapping peptides and by covering all major HLA molecules present in the human population, Louis Picker and colleagues identified ORF UL123 encoding the IE1 protein as one of the top three antigen-encoding ORFs of hCMV that are most frequently detected by HLA class I-restricted human CD8 T cells (L. Picker, "T cell recognition of hCMV in natural human infection: pan-genome analysis of immunogenic open reading frames," Instituto Juan March de Estudios e Investigaciones workshop "Immunodominance: the key to understanding and manipulating CD8 ϩ T cell responses

show abstract

Section: Discussionmentioning

confidence: 52%

Highly Protective In Vivo Function of Cytomegalovirus IE1 Epitope-Specific Memory CD8 T Cells Purified by T-Cell Receptor-Based Cell Sorting

Pahl-Seibert

Juelch

Podlech

et al. 2005

J Virol

105

View full text Add to dashboard Cite

show abstract

“…C, The streptamer complex and the basic principle of the reversible staining technology. TCR, T cell receptor.geneic PBSC transplantation [5,6]. For the identification and quantification of antigen-specific T cells, several multimer techniques have been developed, using tetramers, pentamers [7], and streptamers [8] (figure 1).…”

mentioning

confidence: 99%

“…The viral tegument phosphoprotein 65 has been identified as a major target antigen for CMV-specific, major histocompatibility complex class I-restricted cytotoxic T lymphocytes from the blood of healthy individuals [3][4][5]. Several nonamer or decamer peptides derived from the immunogenic phosphoprotein, CMV phosphoprotein 65 antigen, are specifically recognized by CD8 + cytotoxic T lymphocytes [6]. The frequency of such CMV phosphoprotein 65-specific CD8 + T cells is crucial for patients to achieve CMV clearance after allo- geneic PBSC transplantation [5,6].…”

mentioning

confidence: 99%

“…Several nonamer or decamer peptides derived from the immunogenic phosphoprotein, CMV phosphoprotein 65 antigen, are specifically recognized by CD8 + cytotoxic T lymphocytes [6]. The frequency of such CMV phosphoprotein 65-specific CD8 + T cells is crucial for patients to achieve CMV clearance after allo- geneic PBSC transplantation [5,6]. For the identification and quantification of antigen-specific T cells, several multimer techniques have been developed, using tetramers, pentamers [7], and streptamers [8] (figure 1).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Multimer Staining of Cytomegalovirus Phosphoprotein 65–Specific T Cells for Diagnosis and Therapeutic Purposes: A Comparative Study

et al. 2008

View full text Add to dashboard Cite

These findings demonstrate the power of multimer staining and a certain limitation of serologic testing to define appropriate donors for transplantation. Therefore, whenever possible, CMV-seropositive donors of transplants to seropositive recipients should be screened for their CD8(+) T cell frequency. All 3 multimer technologies can be used, yielding similar results. The streptamer technology additionally offers the advantage of selecting CMV phosphoprotein 65-specific CD8(+) T cells at the good manufacturing practice level for adoptive T cell transfer.

show abstract

“…These algorithms have been combined with those for class I MHC peptide binding [92], and in some cases for TAP transport [93], to predict the peptide antigens most likely to be displayed. This approach has led to the successful identification of several antigens [94][95][96]. …”

mentioning

confidence: 99%

The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes

Engelhard

2007

International Journal of Mass Spectrometry

View full text Add to dashboard Cite

Over the last 15 years, the ability of mass spectrometry to analyze complex peptide mixtures and identify individual species has provided unprecedented insights into the repertoire of peptide antigens displayed by MHC molecules and recognized by T lymphocytes. These include: understanding the peptide binding specificity of MHC molecules; understanding of roles of different intracellular components of the antigen processing pathways in determining the peptide display; and identification of a large number of individual peptide antigens associated with infectious diseases, cancer, and transplant rejection that have provided the basis for new immunologically based therapies. This review will summarize the impact that the application of mass spectrometry has had on these advances, with particular attention to the contributions of Professor Donald Hunt and members of his laboratory, and point out the opportunities for future work. Keywordsantigen processing; post-translational modification; peptides; MHC molecules THE NATURE OF ANTIGEN RECOGNITION BY T LYMPHOCYTEST lymphocytes are a branch of the immune system concerned with recognition of antigens that are displayed on the surface of host cells. These antigens are produced through intracellular proteolytic mechanisms that create small peptides, which are then rescued and presented at the cell surface by adaptor proteins called MHC molecules [reviewed in [1-6]. The binding site of each MHC molecule enables it to bind to a wide range of different peptides, and results in the display of a repertoire of such antigens, each recognized by a distinct T lymphocyte. This "antigen processing and presentation" mechanism results in the display of peptides derived from the proteins of pathogens that have infected the cell or been taken up by endocytosis. Their recognition by T lymphocytes results in the development of an immune response, and results in clearance of the pathogen and infected cells from the body. However, antigen processing and presentation pathways operate constitutively on normal cellular proteins as well, resulting in the display of peptide antigens that can be distinguished on tumors and transplanted tissues. Some of these "self-peptides" are also involved in the development of T lymphocytes in the thymus, and their recognition also controls the balance between selftolerance and autoimmune disease. Correspondence: phone: 434-924-2423; fax: 434-924-1221; email: vhe@virginia.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In most individuals, molecules of each MHC class are expressed from 3 genetic loci that ...

show abstract

A CTL epitope from human cytomegalovirus IE1 defined by combining prediction of HLA binding and proteasomal processing is the target of dominant immune responses in patients after allogeneic stem cell transplantation

Cited by 22 publications

References 47 publications

Highly Protective In Vivo Function of Cytomegalovirus IE1 Epitope-Specific Memory CD8 T Cells Purified by T-Cell Receptor-Based Cell Sorting

Highly Protective In Vivo Function of Cytomegalovirus IE1 Epitope-Specific Memory CD8 T Cells Purified by T-Cell Receptor-Based Cell Sorting

Multimer Staining of Cytomegalovirus Phosphoprotein 65–Specific T Cells for Diagnosis and Therapeutic Purposes: A Comparative Study

The contributions of mass spectrometry to understanding of immune recognition by T lymphocytes

Contact Info

Product

Resources

About