Identification of a human cyclin D1-derived peptide that induces human cytotoxic CD4 T cells.

Abstract

Cyclin D1 is over-expressed in various human tumors and therefore can be a potential oncogenic target antigen. However, only a limited number of T cell epitopes has been characterized. We aimed at identifying human cyclin D1-derived peptides that include both CD4 and CD8 T cell epitopes and to test if such multi-epitope peptides could yield improved cytotoxic CD8 T cell responses as well as cytotoxic CD4 T cells. Five HLA-DR.B1-binding peptides containing multiple overlapping CD4 epitopes and HLA-A0201-restricted CD8 T cell epitopes were predicted by computer algorithms. Immunogenicity of the synthetic peptides was assessed by stimulating T cells from healthy donors in vitro and the epitope recognition was measured by IFN-gamma ELISPOT and (51)Chromium release assays. A HLA-DR.B1 peptide, designed "DR-1", in which a HLA-A0201-binding epitopes (D1-1) was imbedded, induced CD3 T cell responses against both DR-1 and D1-1 peptides in IFN-gamma ELISPOT assay. This suggested processing of the shorter D1-1 epitope from the DR-1 sequence. However, only DR-1-stimulated CD4 or CD3 T cells possessed cytotoxicity against peptide-pulsed autologous DCs and a cancer cell line, that expresses a high level of cyclin D1. Monoclonal antibody to HLA-DR abrogated the epitope-specific responses of both CD3 and CD4 T cells, demonstrating class II-mediated killing. Our studies suggest a possible role of CD4 T cells in anti-tumor immunity as cytotoxic effectors against HLA-DR expressing cancers and provide a rationale for designing peptide vaccines that include CD4 epitopes.

• Authors: Tao Dao, Tatyana Korontsvit, Victoria Zakhaleva, Kurtis Haro, Jonathan Packin, David A Scheinberg
• Journal: PloS one (PLoS One) Vol. 4 Issue 8 Pg. e6730 (Aug 25 2009) ISSN: 1932-6203 [Electronic] United States
• PMID: 19707583 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Histocompatibility Antigens Class I
• Histocompatibility Antigens Class II
• Peptides
• Cyclin D1

Topics

• Amino Acid Sequence
• CD4-Positive T-Lymphocytes (cytology, drug effects, immunology)
• Cell Line, Tumor
• Cyclin D1 (chemistry, metabolism)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Histocompatibility Antigens Class I (immunology)
• Histocompatibility Antigens Class II (immunology)
• Humans
• Molecular Sequence Data
• Peptides (chemistry, pharmacology)
• Phenotype
• T-Lymphocytes, Cytotoxic (cytology, drug effects, immunology)