Cancer testis antigen Cyclin A1 harbors several HLA-A*02:01-restricted T cell epitopes, which are presented and recognized in vivo

Despite the availability of major histocompatibility complex (MHC)-binding peptide prediction algorithms, the development of T-cell vaccines against pathogen and tumor antigens remains challenged by inefficient identification of immunogenic epitopes. CD8+ T cells must distinguish immunogenic epitopes from nonimmunogenic self peptides to respond effectively against an antigen without endangering the viability of the host. Because this discrimination is fundamental to our understanding of immune recognition and critical for rational vaccine design, we interrogated the biochemical properties of 9,888 MHC class I peptides. We identified a strong bias toward hydrophobic amino acids at T-cell receptor contact residues within immunogenic epitopes of MHC allomorphs, which permitted us to develop and train a hydrophobicity-based artificial neural network (ANN-Hydro) to predict immunogenic epitopes. The immunogenicity model was validated in a blinded in vivo overlapping epitope discovery study of 364 peptides from three HIV-1 Gag protein variants. Applying the ANN-Hydro model on existing peptide-MHC algorithms consistently reduced the number of candidate peptides across multiple antigens and may provide a correlate with immunodominance. Hydrophobicity of TCR contact residues is a hallmark of immunogenic epitopes and marks a step toward eliminating the need for empirical epitope testing for vaccine development.

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In-Vivo Generation of Antigen-Specific Tregs with AAV8 Suppresses Collagen-Induced Arthritis in DBA1 Mice through IL-10 Production

10.21203/rs.3.rs-558817/v1 ◽

2021 ◽

Author(s):

Matthew Wade ◽

Hugues Fausther-Bovendo ◽

Marc-Antoine De La Vega ◽

Gary Kobinger

Keyword(s):

T Cell ◽

Autoimmune Diseases ◽

Immune Suppression ◽

Interleukin 10 ◽

T Cell Epitopes ◽

Collagen Induced Arthritis ◽

Adeno Associated Virus ◽

Virus Serotype ◽

Collagen Ii

Abstract Available therapeutics for autoimmune disorders focused on mitigating symptoms, rather than treating the cause of the disorder. A novel approach using adeno-associated virus (AAV) could restore tolerance to the autoimmune targets and provide a permanent treatment for autoimmune diseases. Here, we evaluated the ability of collagen II T-cell epitopes packaged in adeno-associated virus serotype 8 (AAV-8) vectors to reduce pathogenic cellular and humoral responses against collagen and to mitigate the disease in the collagen-induced arthritis mouse model. The cytokines and immune cells involved in the immune suppression were also investigated. Mice treated with AAV-8 containing collagen II T-cell epitopes demonstrated a significant reduction in the arthritis symptoms, pathogenic collagen specific antibody and T cell responses. The AAV-8 mediated immune suppression was mediated by increased interleukin-10 expression and regulatory T cells expansion. Altogether, this study strengthens the notion that AAV vectors are promising candidates for the treatment of autoimmune diseases.

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NS1 DNA vaccination protects against Zika infection through T cell–mediated immunity in immunocompetent mice

Science Advances ◽

10.1126/sciadv.aax2388 ◽

2019 ◽

Vol 5 (12) ◽

pp. eaax2388 ◽

Cited By ~ 12

Author(s):

B. Grubor-Bauk ◽

D. K. Wijesundara ◽

M. Masavuli ◽

P. Abbink ◽

R. L. Peterson ◽

...

Keyword(s):

T Cell ◽

T Cell Response ◽

Viral Envelope ◽

Cell Mediated Immunity ◽

T Cell Epitopes ◽

Vaccine Immunogen ◽

Zikv Infection ◽

Cell Responses ◽

Immunocompetent Mice

The causal association of Zika virus (ZIKV) with microcephaly, congenital malformations in infants, and Guillain-Barré syndrome in adults highlights the need for effective vaccines. Thus far, efforts to develop ZIKV vaccines have focused on the viral envelope. ZIKV NS1 as a vaccine immunogen has not been fully explored, although it can circumvent the risk of antibody-dependent enhancement of ZIKV infection, associated with envelope antibodies. Here, we describe a novel DNA vaccine encoding a secreted ZIKV NS1, that confers rapid protection from systemic ZIKV infection in immunocompetent mice. We identify novel NS1 T cell epitopes in vivo and show that functional NS1-specific T cell responses are critical for protection against ZIKV infection. We demonstrate that vaccine-induced anti-NS1 antibodies fail to confer protection in the absence of a functional T cell response. This highlights the importance of using NS1 as a target for T cell–based ZIKV vaccines.

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