In vivo and in vitro immunogenicity of novel MHC class I presented epitopes to confer protective immunity against chronic HTLV-1 infection

Autor: Xiaofang Huang, Pooja Jain, Edward L. Murphy, Danielle M. Clements, Lishomwa C. Ndhlovu, Aykan Karabudak, Zafar K. Khan, Ria Mulherkar, Aileen G. Rowan, Rashida Ginwala, Ramila Philip
Rok vydání: 2018
Předmět:
0301 basic medicine
Genes
MHC Class I
Medical and Health Sciences
Transgenic
Mass Spectrometry
Epitope
MHC Class I
Mice
Epitopes
2.1 Biological and endogenous factors
Cytotoxic T cell
Aetiology
Human T-lymphotropic virus 1
Tumor
ELISPOT
Hep G2 Cells
Biological Sciences
Flow Cytometry
Infectious Diseases
Molecular Medicine
Female
Infection
Biotechnology
030106 microbiology
Mice
Transgenic
Human leukocyte antigen
Biology
ATLL
Major histocompatibility complex
Article
Cell Line
Vaccine Related
03 medical and health sciences
Rare Diseases
Cell Line
Tumor
Virology
MHC class I
Animals
Humans
Agricultural and Veterinary Sciences
General Veterinary
General Immunology and Microbiology
Public Health
Environmental and Occupational Health
HTLV-I Infections
Immunoproteomics
Granzyme B
Orphan Drug
Good Health and Well Being
030104 developmental biology
Genes
HTLV-1
biology.protein
Immunization
HAM/TSP
Vaccine
CD8
Zdroj: Vaccine, vol 36, iss 33
ISSN: 0264-410X
Popis: Human T-cell leukemia virus type 1 (HTLV-1) has infected approximately 20 million people worldwide. While 90% are asymptomatic, 5% develop severe diseases including adult T-cell leukemia/lymphoka (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). No vaccine against HTLV-1 exists, and screening programs are not universal. However, patients with chronic HTLV-1 infection have high frequencies of HTLV-1-activated CD8+ T cells, and the two main HLA alleles (A2, A24) are present in 88% of infected individuals. We thus utilized an immunoproteomics approach to characterize MHC-I restricted epitopes presented by HLA-A2+, A24+ MT-2 and SLB-1 cell lines. Unlike traditional motif prediction algorithms, this approach identifies epitopes associated with cytotoxic T-cell responses in their naturally processed forms, minimizing differences in antigen processing and protein expression levels. Out of nine identified peptides, we confirmed six novel MHC-I restricted epitopes that were capable of binding HLA-A2 and HLA-A24 alleles and used in vitro and in vivo methods to generate CD8+ T cells specific for each of these peptides. MagPix MILLIPLEX data showed that in vitro generated epitope-specific CD8+ T cells secreted IFN-γ, granzyme B, MIP-1α, TNF-α, perforin and IL-10 when cultured in the presence of MT-2 cell line. Degranulation assay confirmed cytotoxic response through surface expression of CD107 on CD8+ T cells when cultured with MT-2 cells. A CD8+ T-cell killing assay indicated significant antiviral activity of CD8+ T cells specific against all identified peptides. In vivo generated CD8+ T cells similarly demonstrated immunogenicity on ELISpot, CD107 degranulation assay, and MagPix MILLIPLEX analysis. These epitopes are thus candidates for a therapeutic peptide-based vaccine against HTLV-1, and our results provide preclinical data for the advancement of such a vaccine.
Databáze: OpenAIRE
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