Clonal diversity of the T-cell population responding to a dominant HLA-A2 epitope of HER-2/neu after active immunization in an ovarian cancer patient

Keith L Knutson, Mary L. Disis

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Natural antigen processing and presentation of antigen is thought to be important for the generation of a broad functional repertoire of antigen-specific T cells. In this study, the T-cell repertoire to an immunodominant human leukocyte antigen A2 (HLA-A2) binding peptide epitope of HER-2/neu, p369-377, was examined in a patient following immunization with a peptide-based vaccine consisting of helper peptides encompassing HLA-A2 peptide epitopes. The responding T-cell repertoire generated was both phenotypically and functionally diverse. A total of 21 p369-377 clones were generated from this patient. With the exception of two clones, all clones were CD3+. Sixteen of the clones were CD8+/CD4-. Five of the clones were CD4+/CD8-, despite being generated with an HLA-A2 binding peptide. Nineteen of 21 of clones expressed the αβ-T-cell receptor (TCR). The remaining two clones expressed the γδ T-cell response (TCR). Selected αβ-TCR clones, both CD8+ and CD4+, could lyse HLA-A2 transfected HER2 over-expressing tumor cells and p369-377-loaded B-lymphoblastic cell line. In addition to their lytic capabilities these clones could be induced to produce interferon-γ (IFN-γ) specifically in response to p369-377 peptide stimulation. The 2 γδ-TCR clones expressed CD8 and lysed HLA-A2+ HER-2/neu tumor cells, but not HLA-A2- HER-2/neu+ tumor cells. One of γδ-TCR clones also released IFN-γ directly in response to p369-377 stimulation. These results suggest that a tumor antigen TCR, directed against a specific epitope, can be markedly polyclonal at multiple levels including CD4/CD8 and TCR.

Original languageEnglish (US)
Pages (from-to)547-557
Number of pages11
JournalHuman Immunology
Volume63
Issue number7
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

HLA Antigens
varespladib methyl
Ovarian Neoplasms
Epitopes
Vaccination
Clone Cells
T-Lymphocytes
T-Cell Antigen Receptor
Population
Antigen Presentation
Interferons
Peptides
Antigens
Neoplasms
Subunit Vaccines
Neoplasm Antigens
Immunization
Cell Line

Keywords

  • γδ T cells
  • CTL
  • T lymphocytes
  • Tumor immunity
  • Vaccination

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

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title = "Clonal diversity of the T-cell population responding to a dominant HLA-A2 epitope of HER-2/neu after active immunization in an ovarian cancer patient",
abstract = "Natural antigen processing and presentation of antigen is thought to be important for the generation of a broad functional repertoire of antigen-specific T cells. In this study, the T-cell repertoire to an immunodominant human leukocyte antigen A2 (HLA-A2) binding peptide epitope of HER-2/neu, p369-377, was examined in a patient following immunization with a peptide-based vaccine consisting of helper peptides encompassing HLA-A2 peptide epitopes. The responding T-cell repertoire generated was both phenotypically and functionally diverse. A total of 21 p369-377 clones were generated from this patient. With the exception of two clones, all clones were CD3+. Sixteen of the clones were CD8+/CD4-. Five of the clones were CD4+/CD8-, despite being generated with an HLA-A2 binding peptide. Nineteen of 21 of clones expressed the αβ-T-cell receptor (TCR). The remaining two clones expressed the γδ T-cell response (TCR). Selected αβ-TCR clones, both CD8+ and CD4+, could lyse HLA-A2 transfected HER2 over-expressing tumor cells and p369-377-loaded B-lymphoblastic cell line. In addition to their lytic capabilities these clones could be induced to produce interferon-γ (IFN-γ) specifically in response to p369-377 peptide stimulation. The 2 γδ-TCR clones expressed CD8 and lysed HLA-A2+ HER-2/neu tumor cells, but not HLA-A2- HER-2/neu+ tumor cells. One of γδ-TCR clones also released IFN-γ directly in response to p369-377 stimulation. These results suggest that a tumor antigen TCR, directed against a specific epitope, can be markedly polyclonal at multiple levels including CD4/CD8 and TCR.",
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AU - Disis, Mary L.

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N2 - Natural antigen processing and presentation of antigen is thought to be important for the generation of a broad functional repertoire of antigen-specific T cells. In this study, the T-cell repertoire to an immunodominant human leukocyte antigen A2 (HLA-A2) binding peptide epitope of HER-2/neu, p369-377, was examined in a patient following immunization with a peptide-based vaccine consisting of helper peptides encompassing HLA-A2 peptide epitopes. The responding T-cell repertoire generated was both phenotypically and functionally diverse. A total of 21 p369-377 clones were generated from this patient. With the exception of two clones, all clones were CD3+. Sixteen of the clones were CD8+/CD4-. Five of the clones were CD4+/CD8-, despite being generated with an HLA-A2 binding peptide. Nineteen of 21 of clones expressed the αβ-T-cell receptor (TCR). The remaining two clones expressed the γδ T-cell response (TCR). Selected αβ-TCR clones, both CD8+ and CD4+, could lyse HLA-A2 transfected HER2 over-expressing tumor cells and p369-377-loaded B-lymphoblastic cell line. In addition to their lytic capabilities these clones could be induced to produce interferon-γ (IFN-γ) specifically in response to p369-377 peptide stimulation. The 2 γδ-TCR clones expressed CD8 and lysed HLA-A2+ HER-2/neu tumor cells, but not HLA-A2- HER-2/neu+ tumor cells. One of γδ-TCR clones also released IFN-γ directly in response to p369-377 stimulation. These results suggest that a tumor antigen TCR, directed against a specific epitope, can be markedly polyclonal at multiple levels including CD4/CD8 and TCR.

AB - Natural antigen processing and presentation of antigen is thought to be important for the generation of a broad functional repertoire of antigen-specific T cells. In this study, the T-cell repertoire to an immunodominant human leukocyte antigen A2 (HLA-A2) binding peptide epitope of HER-2/neu, p369-377, was examined in a patient following immunization with a peptide-based vaccine consisting of helper peptides encompassing HLA-A2 peptide epitopes. The responding T-cell repertoire generated was both phenotypically and functionally diverse. A total of 21 p369-377 clones were generated from this patient. With the exception of two clones, all clones were CD3+. Sixteen of the clones were CD8+/CD4-. Five of the clones were CD4+/CD8-, despite being generated with an HLA-A2 binding peptide. Nineteen of 21 of clones expressed the αβ-T-cell receptor (TCR). The remaining two clones expressed the γδ T-cell response (TCR). Selected αβ-TCR clones, both CD8+ and CD4+, could lyse HLA-A2 transfected HER2 over-expressing tumor cells and p369-377-loaded B-lymphoblastic cell line. In addition to their lytic capabilities these clones could be induced to produce interferon-γ (IFN-γ) specifically in response to p369-377 peptide stimulation. The 2 γδ-TCR clones expressed CD8 and lysed HLA-A2+ HER-2/neu tumor cells, but not HLA-A2- HER-2/neu+ tumor cells. One of γδ-TCR clones also released IFN-γ directly in response to p369-377 stimulation. These results suggest that a tumor antigen TCR, directed against a specific epitope, can be markedly polyclonal at multiple levels including CD4/CD8 and TCR.

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