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Trans-splicing of class I HLA bound peptides diversifies the immunopeptidome

ABSTRACT: The diversity of peptides displayed by class I HLA plays an essential role in T cell immunity. The peptide repertoire is extended by various post-translational modifications, including cis-splicing of peptides from the same protein. Here, we have applied a novel bioinformatic workflow and demonstrate that spliced-peptides are also generated through trans-splicing (fusion of peptide segments from distinct antigens) and their abundance challenges current models of proteasomal-splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA binding motif sequence features. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design and immunotherapy.

INSTRUMENT(S): TripleTOF 5600, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Pouya Faridi

LAB HEAD: Anthony Purcell

PROVIDER: PXD017922 | Pride | 2021-12-06

REPOSITORIES: pride

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			Action	DRS
	20140205_SR_B0702_gp160_A1.mzxml	Mzxml
	20140205_SR_B0702_gp160_A10.mzxml	Mzxml
	20140205_SR_B0702_gp160_A11.mzxml	Mzxml
	20140205_SR_B0702_gp160_A12.mzxml	Mzxml
	20140205_SR_B0702_gp160_A13.mzxml	Mzxml

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Trans-splicing of class I HLA bound peptides diversifies the immunopeptidome

Project description:The diversity of peptides displayed by class I HLA plays an essential role in T cell immunity. The peptide repertoire is extended by various post-translational modifications, including cis-splicing of peptides from the same protein. Here, we have applied a novel bioinformatic workflow and demonstrate that spliced-peptides are also generated through trans-splicing (fusion of peptide segments from distinct antigens) and their abundance challenges current models of proteasomal-splicing that predict cis-splicing as the most probable outcome. These trans-spliced peptides display canonical HLA binding motif sequence features. These results highlight the unanticipated diversity of the immunopeptidome and have important implications for autoimmunity, vaccine design and immunotherapy.

2018-10-16 | PXD009660 | Pride

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Project description:Peptides generated by proteasome-catalyzed splicing of non-contiguous amino acid sequences have been shown to constitute a source of non-templated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8+ T cells are key mediators of human immunodeficiency virus type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly-applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a novel, but relatively minor, component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8+ T cell responses relatively infrequently during infection, CD8+ T cells primed by partially-overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically under-utilized during natural infection.

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