Functional characterization of EBV-encoded nuclear antigen 1-specific CD4+ helper and regulatory T cells elicited by in vitro peptide stimulation.
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.
Voo
Kui Shin
KS
The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, Texas, USA.
Peng
Guangyong
G
Guo
Zhong
Z
Fu
Tihui
T
Li
Yanchun
Y
Frappier
Lori
L
Wang
Rong-Fu
RF
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002144:Callithrix; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D019309:Epstein-Barr Virus Nuclear Antigens; D006684:HLA-DR Antigens; C417029:EBV-encoded nuclear antigen 1