Human CD4(+) T cells recognize an epitope within alpha-fetoprotein sequence and develop into TGF-beta-producing CD4(+) T cells.
There is limited information on the influence of tumor growth on the expansion of tumor-specific TGF-beta-producing CD4(+) T cells in humans. alpha-Fetoprotein (AFP) is an oncofetal Ag and has intrinsic immunoregulatory properties. In this study, we report the identification and characterization of subsets of CD4(+) T cells that recognize an epitope within the AFP sequence (AFP(46-55)) and develop into TGF-beta-producing CD4(+) T cells. In a peptide-specific and dose-dependent manner, AFP(46-55) CD4(+) T cells produce TGF-beta, GM-CSF, and IL-2 but not Th1-, Th2-, Th17-, or Tr1-type cytokines. These cells express CTLA-4 and glucocorticoid-induced TNR receptor and inhibit T cell proliferation in a contact-dependent manner. In this study, we show that the frequency of AFP(46-55) CD4(+) T cells is significantly higher (p = 001) in patients with hepatocellular carcinoma than in healthy donors, suggesting that these cells are expanded in response to tumor Ag. In contrast, tumor necrosis-inducing treatments that are shown to improve survival rate can shift the Th1/TGF-beta-producing CD4(+) T cell balance in favor of Th1 responses. Our data demonstrate that tumor Ags may contain epitopes which activate the expansion of inducible regulatory T cells, leading to evasion of tumor control.
Alisa
Akeel
A
Department of Medicine, Institute of Hepatology, University College London, London, UK.
Boswell
Sandra
S
Pathan
Ansar A
AA
Ayaru
Lakshmana
L
Williams
Roger
R
Behboudi
Shahriar
S
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D060908:CTLA-4 Antigen; D006528:Carcinoma, Hepatocellular / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010641:Phenotype; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D000509:alpha-Fetoproteins / Q000737:chemistry* / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000939:Epitopes; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D000509:alpha-Fetoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor