Quantitation of Lysozyme Peptides Bound to Class II MHC Molecules Indicates Very Large Differences in Levels of Presentation

Velázquez, Carlos; DiPaolo, Richard J.; Unanue, Emil R.

doi:10.4049/jimmunol.166.9.5488

Cited by 41 publications

(51 citation statements)

References 31 publications

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“…These results contrast with the earlier studies mentioned above, but agree with the more recent findings in DM-deficient mice bearing the H-2 k haplotype (13) while extending the findings to all four HEL epitopes presented by I-A k . In summary, in the presence of DM there is a gradient of HEL peptides bound to I-A k with a pronounced skewing to the chemically dominant peptide family centered around core residues 52-60 that form a high affinity, long-lived (t 1/2 Ͼ 96 h) interaction with the I-A k binding cleft (1). The other three peptide families (31-47, 20 -35, and 114 -129) are presented at much lower levels.…”

Section: Resultsmentioning

confidence: 99%

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Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing

Lovitch

Petzold

Unanue

2003

The Journal of Immunology

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We quantitated the amounts of peptides from hen egg-white lysozyme presented by I-Ak molecules in APC lines. The large chemical gradient of presentation of the four hen egg-white lysozyme epitopes observed in cell lines expressing HLA-DM or H-2DM (referred to in this study as DM) was significantly diminished in the T2.Ak line lacking DM. Differences in levels of presentation between wild-type and DM-deficient APC were observed for all four epitopes, but differences were most evident for the highest affinity epitope. As a result of these quantitative differences in display, presentation of all four epitopes to T cells was impaired in the line lacking DM. The binding affinity of the pool of naturally processed peptides from DM-expressing lines was higher than that from the DM-deficient line. Thus, using a direct biochemical approach in APC, we demonstrate that DM influences the selection of peptides bound to MHC class II by favoring high affinity peptides.

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Section: Resultsmentioning

confidence: 99%

“…Synthetic peptides representing the major member of each of the four HEL peptide families ( Fig. 1) were produced in our laboratory (1).…”

Section: Methodsmentioning

confidence: 99%

Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing

Lovitch

Petzold

Unanue

2003

The Journal of Immunology

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“…MV-derived immunogenic peptides are generated in extremely low levels, and experimental data have shown the importance of peptide abundance in the development of an immune response (40,48,49). Nevertheless, these low levels of class II peptides are sufficient to elicit an effective CD4 ϩ T-cell response against foreign peptides (47).…”

Section: Vol 78 2004 Naturally Processed MV Class Ii Peptides 47mentioning

confidence: 99%

Identification and Characterization of Novel, Naturally Processed Measles Virus Class II HLA-DRB1 Peptides

Ovsyannikova

Johnson²,

Muddiman³

et al. 2004

J Virol

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Previously, we identified a naturally processed and presented measles virus (MV) 19-amino-acid peptide, ASDVETAEGGEIHELLRLQ (MV-P), derived from the phosphoprotein and eluted from the human leukocyte antigen (HLA) class II molecule by using mass spectrometry. We report here the identification of a 14-aminoacid peptide, SAGKVSSTLASELG, derived from the MV nucleoprotein (MV-N) bound to HLA-DRB1*0301. Peripheral blood mononuclear cells (PBMC) from 281 previously vaccinated measles-mumps-rubella II (MMR-II) subjects (HLA discordant) were studied for peptide recognition by T cells. Significant gamma interferon (IFN-␥) responses to MV-P and MV-N peptides were observed in 55.9 and 15.3% of subjects, respectively. MV-P-and MV-N-specific interleukin-4 (IL-4) responses were detected in 19.2 and 23.1%, respectively, of PBMC samples. Peptide-specific cytokine responses and HLA-DRB1 allele associations revealed that, for the MV-P peptide, the allele with the strongest association with both IFN-␥ (P ‫؍‬ 0.02) and IL-4 (P ‫؍‬ 0.03) secretion was DRB1*0301. For MV-N, the allele with the strongest association with IFN-␥ secretion was DRB1*1501 (P ‫؍‬ 0.04), and the alleles with the strongest associations with IL-4 secretion were DRB1*1103 and DRB1*1303 (P ‫؍‬ 0.01). These results indicate that HLA class II MV proteins can be processed, presented, and identified, and the ability to generate cell-mediated immune responses can be demonstrated. This information is promising for new vaccine design strategies with peptide-based vaccines.

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“…A tryptophan at residue 62 also serves as a TCR contact to some T cells (38). There is minor peptide family, expressed at Ϸ1͞200th the amount as those of the 52-60 family, encompassing residues 20-35 (YTGY SLGNWVCAA KFE) (34,37). The core segment centers on residues 24-32 are in bold.…”

Section: Generation Of T Cells To Modifiedmentioning

confidence: 99%

Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells

Herzog

Maekawa

Cirrito

et al. 2005

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

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CD4 T cells recognized posttranslationally modified peptides of the protein hen egg-white lysozyme (HEL), consisting of nitration of tyrosines and modifications of tryptophans in the T cell contact residues of the peptides. T cells were directed against modifications of a chemically dominant HEL peptide as well as a minor HEL peptide, bound to the class II histocompatibility molecule I-A k . The modified peptides were generated in vivo after immunization with native HEL molecules or were generated ex vivo by peroxynitrite treatment of HEL. Moreover, antigen-presenting cells (APC), either macrophages or dendritic cells activated in culture or in vivo, generated the modified HEL epitopes that stimulated the T cells. In transgenic mice expressing HEL, the T cells to the modified epitopes escaped negative selection and were found, albeit fewer in number than in normal mice. Infection with Listeria monocytogenes of the transgenic HEL mice generated APC containing the modifications. T cells to modified epitopes induced by activation of APC may be a component of antimicrobial immunity and autoimmune reactions.histocompatability molecules ͉ nitrotyrosine ͉ posttranslational modification P eptides bound to either class I or class II MHC molecules suffer posttranslational modifications of potential importance in the context of inducing unique T cell reactivities. A number of posttranslational changes were identified on peptides isolated from class I MHC proteins (1, 2), including phosphorylation of tyrosine residues (3). Unique T cell reactivities were ascribed to changes in the peptides bound to class II MHC molecules (reviewed in ref. 4). These included phosphorylations (5), conversions of asparagine or aspartic acid to isoaspartic acid (6, 7), glutamine to glutamic acid (8, 9), nitration of tyrosine (10), and addition of saccharide residues to a peptide (11-15). These results are reminiscent of early ones showing T cell reactions to proteins containing small reactive chemical groups, i.e., with ''haptens,'' first reported by Jones and Leskowitz (16) in delayed sensitivity reactions to arsanilic acid. Their observations were extended by others (17), including by using dinitrophenyl to derivatize class II molecules on cells (18). Clearly, T cells are highly discriminatory of large or small changes in the residues to which their receptor [T cell receptor (TCR)] establishes contact. Antibodies directed to posttranslationally modified proteins have also been identified (19,20).Activation of macrophages and dendritic cells (DC) takes place after their interactions with IFN-␥ together with cytokines like TNF or IL-1, or microbial products like LPS from Gram-negative bacteria. The activation includes the production of nitric oxide (NO) and reactive oxygen species with the formation of strong oxidizing molecules such as peroxynitrite (21-23) or other derivatives (24,25). These molecules induce a number of amino acid changes, including nitration of tyrosines (21, 22) and modification of tryptophans (26). The present study report...

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Quantitation of Lysozyme Peptides Bound to Class II MHC Molecules Indicates Very Large Differences in Levels of Presentation

Cited by 41 publications

References 31 publications

Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing

Cutting Edge: H-2DM Is Responsible for the Large Differences in Presentation Among Peptides Selected by I-Ak During Antigen Processing

Identification and Characterization of Novel, Naturally Processed Measles Virus Class II HLA-DRB1 Peptides

Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells

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