Enhanced expression of lymphotactin by CD8+ T cells is selectively induced by enhancer agonist peptides of tumor-associated antigens.
Human tumor-associated antigens (TAAs) are weak immunogens. One strategy for increasing the immunogenicity of TAAs is to generate altered peptide ligands. In the studies reported here, microarray technology has been used to compare gene expression profiles of a human T cell line that was derived from the peripheral blood of a cancer patient vaccinated with a carcinoembryonic antigen (CEA)-based vaccine. We compared the gene expression profiles of this CEA-specific CD8 T cell line when (a) stimulated with the native peptide used to derive this line vs. no peptide, and (b) stimulated with its TCR enhancer agonist epitope vs. no peptide. The results demonstrate that the effect on the T cell line, when stimulated with the agonist peptide, is not an enhanced quantitative expression of the same genes or gene sets induced by the native peptide, but is rather a nearly reciprocal upregulation of different gene sets. The gene for the chemokine lymphotactin, which was overexpressed only in T cells stimulated with the agonist peptide, stood out above all others. This finding was extended using other T cell lines, and another set of agonist and native peptides from another TAA. ELISPOT and ELISA assays for lymphotactin confirmed and extended these findings. These studies suggest a potential role for lymphotactin in the T-cell activation processes and subsequent anti-tumor events.
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Claudia
C
Palena
Philip
P
Arlen
Hasan
H
Zeytin
John W
JW
Greiner
Jeffrey
J
Schlom
Kwong-Yok
KY
Tsang
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002460:Cell Line; D019744:Chemokines, C / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D018920:Coculture Techniques; D003208:Concanavalin A / Q000494:pharmacology; D015536:Down-Regulation; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018396:Mucin-1 / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D011506:Proteins / Q000032:analysis; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation
D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D019744:Chemokines, C; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D018396:Mucin-1; D010446:Peptide Fragments; D011506:Proteins; C092390:XCL1 protein, human; C486249:Xcl1 protein, mouse; D003208:Concanavalin A; D007371:Interferon-gamma