Functional characterization of EBV-encoded nuclear antigen 1-specific CD4+ helper and regulatory T cells elicited by in vitro peptide stimulation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-02, Vol.65 (4), p.1577-1586
• Main Authors: KUI SHIN VOO, GUANGYONG PENG, ZHONG GUO, TIHUI FU, YANCHUN LI, FRAPPIER, Lori, WANG, Rong-Fu
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic agents; Biological and medical sciences; Callithrix; CD4-Positive T-Lymphocytes - immunology; Epitopes, T-Lymphocyte - immunology; Epstein-Barr Virus Nuclear Antigens - immunology; HLA-DR Antigens - immunology; Humans; Lymphocyte Activation - immunology; Medical sciences; Molecular Sequence Data; Pharmacology. Drug treatments; T-Lymphocytes, Helper-Inducer - immunology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-2552

CD4(+) helper and regulatory T (Treg) cells play important but opposing roles in regulating host immune responses against cancer and other diseases. However, very little is known about the antigen specificity of CD4(+) Treg cells. Here we describe the generation of a panel of EBV-encoded nuclear antigen 1 (EBNA1)-specific CD4(+) T-cell lines and clones that recognize naturally processed EBNA1-P(607-619) and -P(561-573) peptides in the context of HLA-DQ2 and HLA-DR11, -DR12, and -DR13 molecules, respectively. Phenotypic and functional analyses of these CD4(+) T cells revealed that they represent EBNA1-specific CD4(+) T helper as well as Treg cells. CD4(+) Treg cells do not secrete interleukin (IL)-10 and transforming growth factor beta cytokines but express CD25, the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), and Forkhead Box P3 (Foxp3), and are capable of suppressing the proliferative responses of naive CD4(+) and CD8(+) T cells to stimulation with mitogenic anti-CD3 antibody. The suppressive activity of these CD4(+) Treg cells is mediated via cell-cell contact or in part by a cytokine-dependent manner. Importantly, these Treg cells suppress IL-2 secretion by CD4(+) effector T cells specific for either EBNA1 or a melanoma antigen, suggesting that these CD4(+) Treg cells induce immune suppression. These observations suggest that the success of peptide-based vaccines against EBV-associated cancer and other diseases may likely depend upon our ability to identify antigens/peptides that preferentially activate helper T cells and/or to design strategies to regulate the balance between CD4(+) helper and Treg cells.