Post-translational modifications of naturally processed MHC-binding epitopes

Engelhard, Víctor H.; Altrich-VanLith, Michelle L.; Ostankovitch, Marina; Zarling, Angela L.

doi:10.1016/j.coi.2005.11.015

Cited by 105 publications

(94 citation statements)

References 54 publications

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“…2) Stabilization of the protein-MHC complex by protrusion of the lipid moiety from the MHC class II-binding groove and attachment to the phospholipid bilayer of the endosomal membrane (86). 3) Unmasking or modification of protein epitopes by posttranslational lipidation thereby increasing the repertoire of peptides fitting into the MHC-binding groove (87). Further knowledge about the contribution of the lipid anchor for the immunogenicity of lipopeptides may open new avenues for the rational design of new vaccines.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Bastian¹,

Braun

Bruns³

et al. 2008

The Journal of Immunology

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In searching for immunogenic molecules with the potential to induce protective immune responses against tuberculosis, we developed an ex vivo model to study frequency, phenotype, and effector functions of human T lymphocytes recognizing hydrophobic Ags of Mycobacterium tuberculosis (M.Tb). To obtain unbiased results, we characterized T lymphocytes responding to a crude cell wall extract (chloroform methanol extract of M.Tb (M.Tb-CME)) containing a broad spectrum of mycobacterial glycolipids and lipopeptides. A significant proportion of T lymphocytes recognized M.Tb-CME (290 IFN-γ+ T cells/105 PBMCs) and developed to effector memory cells as determined by the expression of CD45RO and the chemokine receptors CXCR3 and CCR5. Expanded lymphocytes fulfilled all criteria required for an efficient immune response against tuberculosis: 1) release of macrophage-activating Th1 cytokines and chemokines required for the spatial organization of local immune responses, 2) cytolytic activity against Ag-pulsed macrophages, and 3) recognition of infected macrophages and killing of the intracellular bacteria. Phenotypically, M.Tb-CME-expanded cells were CD4+ and MHC class II restricted, challenging current concepts that cytotoxic and antimicrobial effector cells are restricted to the CD8+ T cell subset. Pretreatment of M.Tb-CME with protease or chemical delipidation abrogated the biological activity, suggesting that responses were directed toward mycobacterial lipopeptides. These findings suggest that lipidated peptides are presented by M.Tb-infected macrophages and elicit CD4+ cytolytic and antimicrobial T lymphocytes. Our data support an emerging concept to include hydrophobic microbial Ags in vaccines against tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Bastian¹,

Braun

Bruns³

et al. 2008

The Journal of Immunology

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“…A variety of posttranslational modifications have been identified on naturally processed MHC class II-associated epitopes. These include N-and O-linked glycosylation, N-terminal acetylation, nitration, deamidation, and deimination/citrullination (18). Although an early attempt to detect phosphorylation on class II MHC peptides met with failure (5), new technology has now made it possible to observe this modification as well (19).…”

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confidence: 99%

Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy

Depontieu

Qian²,

Zarling

et al. 2009

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

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The activation and recruitment of CD4 ؉ T cells are critical for the development of efficient antitumor immunity and may allow for the optimization of current cancer immunotherapy strategies. Searching for more optimal and selective targets for CD4 ؉ T cells, we have investigated phosphopeptides, a new category of tumorderived epitopes linked to proteins with vital cellular functions. Although MHC I-restricted phosphopeptides have been identified, it was previously unknown whether human MHC II molecules present phosphopeptides for specific CD4 ؉ T cell recognition. We first demonstrated the fine specificity of human CD4 ؉ T cells to discriminate a phosphoresidue by using cells raised against the candidate melanoma antigen mutant B-Raf or its phosphorylated counterpart. Then, we assessed the presence and complexity of human MHC II-associated phosphopeptides by analyzing 2 autologous pairs of melanoma and EBV-transformed B lymphoblastoid lines. By using sequential affinity isolation, biochemical enrichment, mass spectrometric sequencing, and comparative analysis, a total of 175 HLA-DR-associated phosphopeptides were characterized. Many were derived from source proteins that may have roles in cancer development, growth, and metastasis. Most were expressed exclusively by either melanomas or transformed B cells, suggesting the potential to define cell type-specific phosphatome ''fingerprints.'' We then generated HLA-DR␤1 * 0101-restricted CD4 ؉ T cells specific for a phospho-MART-1 peptide identified in both melanoma cell lines. These T cells showed specificity for phosphopeptide-pulsed antigen-presenting cells as well as for intact melanoma cells. This previously undescribed demonstration of MHC II-restricted phosphopeptides recognizable by human CD4 ؉ T cells provides potential new targets for cancer immunotherapy.tumor antigen ͉ tumor immunology

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“…159 Thus, verification of in vitro proteasomal C-terminal generation predicts the intracellular generation of most class I ligands, but will miss those that are C-terminally liberated by other enzymes. An additional category of class I ligands being missed by reverse immunology are peptides that are post-translationally modified 89,90 or produced intracellularly by uncommon mechanisms like peptide splicing. 48,49 In summary, when applying experimental verifications with stringent selection criteria in the prediction phase, reverse immunology is extremely well suited to successfully predict HLA class I-presented ligands of which the immunogenicity is sometimes hard to confirm (or absent) due to absence of specific T cells.…”

Section: Efficiency Of Reverse Immunologymentioning

confidence: 99%

“…[83][84][85][86][87][88] Subsequently, database searches may identify the unknown source antigen. [85][86][87][88] A particular advantage of this strategy is that it may identify post-translationally modified epitopes 89,90 (or special epitopes generated by protein/peptide splicing 48,49,91 ). Still another way to analyse the specificity of pre-existing CTL clones is the application of synthetic peptide libraries to search for reactive mimicry epitopes.…”

Section: Identification Of Ctl Epitopes Starting With Ctl Of Unknown mentioning

confidence: 99%

Identification of T-cell epitopes for cancer immunotherapy

2007

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The effectiveness of T-cell-mediated immunotherapy of cancer depends on both an optimal immunostimulatory context of the therapy and the proper selection with respect to quality and quantity of the targeted tumor-associated antigens (TAA), and, more precisely, the T-cell epitopes contained in these tumor proteins. Our progressing insight in human leukocyte antigen (HLA) class I and class II antigen processing and presentation mechanisms has improved the prediction by reverse immunology of novel cytotoxic T lymphocyte and T-helper cell epitopes within known antigens. Computer algorithms that in silico predict HLA class I and class II binding, proteasome cleavage patterns and transporter associated with antigen processing translocation are now available to expedite epitope identification. The advent of genomics allows a high-throughput screening for tumor-specific transcripts and mutations, with that identifying novel shared and unique TAA. The increasing power of mass spectrometry and proteomics will lead to the direct identification from the tumor cell surface of numerous novel tumor-specific HLA class I and class II presented ligands. Together, the expanded repertoire of tumor-specific T-cell epitopes will enable more precise immunomonitoring and the development of effective epitope-defined adoptive T-cell transfer and multi-epitope-based vaccination strategies targeting epitopes derived from a wider diversity of TAA presented in a broader array of HLA molecules.

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Post-translational modifications of naturally processed MHC-binding epitopes

Cited by 105 publications

References 54 publications

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

Identification of tumor-associated, MHC class II-restricted phosphopeptides as targets for immunotherapy

Identification of T-cell epitopes for cancer immunotherapy

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