Dataset Information

Identification of a First Human Norovirus CD8+ T Cell Epitope Restricted to HLA-A*0201 Allele.

ABSTRACT: Norovirus (NoV) causes a substantial global burden of acute gastroenteritis in all age groups and the development of NoV vaccine is a high priority. There are still gaps in understanding of protective NoV-specific immunity. Antibody mediated immune responses have been widely studied, but in contrast, the research on NoV-specific human T cell-mediated immunity is very limited. We have recently reported NoV capsid VP1-specific 18-mer peptide (134SPSQVTMFPHIIVDVRQL151) to induce strong CD8+ T cell immune responses in healthy adult donors. This work extends to identify the precise NoV T cell epitope and the restricting human leucocyte antigen (HLA). Pentamer technology was used to detect HLA-A*0201-restricted T cell-mediated responses to 10-mer peptide 139TMFPHIIVDV148 of four healthy adult blood donors. Immunogenicity of the 10-mer epitope was confirmed by ELISPOT IFN-? and intracellular cytokine staining (ICS) on flow cytometry. A population of CD3+CD8+ T lymphocytes binding to HLA-A*0201/TMFPHIIVDV pentamers was identified in two HLA-A*0201-positive donors. Recognition of the 10-mer epitope by T cells resulted in a strong IFN-? secretion as shown by ELISPOT assay. In addition, ICS confirmed that high proportion (31 and 59%) of the TMFPHIIVDV epitope-responsive CD3+CD8+ T cells in the two donors had multifunctional phenotype, simultaneously producing IFN-?, IL-2 and TNF-? cytokines. In the present study novel human NoV HLA-A*0201-restricted minimal 10-mer epitope 139TMFPHIIVDV148 in the capsid VP1 was identified. The HLA-peptide pentamer staining of T cells from healthy donor PBMCs and cytokine responses in ex-vivo ELISPOT and ICS assays suggest that this epitope is recognized during NoV infection and activates memory phenotype of the epitope-specific multifunctional CD8+ T cells. The importance of this epitope in protection from NoV infection remains to be determined.

SUBMITTER: Malm M

PROVIDER: S-EPMC6277766 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Identification of a First Human Norovirus CD8+ T Cell Epitope Restricted to HLA-A*0201 Allele.

Malm Maria M Vesikari Timo T Blazevic Vesna V

Frontiers in immunology 20181127

Norovirus (NoV) causes a substantial global burden of acute gastroenteritis in all age groups and the development of NoV vaccine is a high priority. There are still gaps in understanding of protective NoV-specific immunity. Antibody mediated immune responses have been widely studied, but in contrast, the research on NoV-specific human T cell-mediated immunity is very limited. We have recently reported NoV capsid VP1-specific 18-mer peptide (134SPSQVTMFPHIIVDVRQL151) to indu ...[more]

PMID: 30542352

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Project description:BACKGROUND: All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8(+) T cells are involved in controlling DV infection. Serotype cross-reactive CD8(+) T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity in vivo and cross-reactivity within heterologous peptides. METHODS: D1V-derived candidate CD8(+) T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice. RESULTS: Of the seven D1V-derived candidate epitopes [D1V-NS4a(56-64)(MLLALIAVL), D1V-C(46-54)(LVMAFMAFL), D1V-NS4b(562-570)(LLATSIFKL), D1V-NS2a(169-177)(AMVLSIVSL), D1V-NS4a(140-148)(GLLFMILTV), D1V-NS2a(144-152)(QLWAALLSL) and D1V-NS4b(183-191)(LLMRTTWAL)], three peptides [D1V-NS4a(140-148), D1V-NS2a(144-152) and D1V-NS4b(183-191)] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a(140-148)(AILTVVAAT), D3V-NS4a(140-148)(GILTLAAIV), D4V-NS4a(140-148)(TILTIIGLI), D2V-NS2a(144-152)(QLAVTIMAI), D3V-NS2a(144-152)(QLWTALVSL), D4V-NS2a(143-151)(QVGTLALSL), D2V-NS4b(182-190)(LMMRTTWAL), D3V-NS4b(182-190) (LLMRTSWAL) and D4V-NS4b(179-187)(LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8+ T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b(183-191), D2V-NS4b(182-190), D3V-NS4b(182-190) and D4V-NS4b(179-187)) was observed. CONCLUSIONS: Two novel serotype-specific HLA-A*0201-restricted CD8(+) T-cell epitopes (NS4a(140-148) and NS2a(144-152)) and one cross-reactive HLA-A*0201-restricted CD8(+) T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8(+) T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8(+) T cells in the immunopathogenesis of DHF/DSS.

Dataset Information

Identification of a First Human Norovirus CD8+ T Cell Epitope Restricted to HLA-A*0201 Allele.

Publications

Identification of a First Human Norovirus CD8<sup>+</sup> T Cell Epitope Restricted to HLA-A<sup>*</sup>0201 Allele.

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