Depletion of CD25+CD4+T cells (Tregs) enhances the HBV-specific CD8+ T cell response primed by DNA immunization.
OBJECTIVE
Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8(+) T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25(+)CD4(+) regulatory T (Treg) cells might be involved in a inhibition of CD8(+) T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8(+) T cell response primed by DNA immunization.


METHODS
B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 microg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25(+) cells. Induction of HBV-specific CD8(+) T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-gamma staining.


RESULTS
DNA immunization induced HBV-specific CD8(+) T cells. At the peak T cell response (d 10), 7.1+/-2.0% of CD8(+) T cells were HBV-specific after DNA immunization, whereas 12.7+/-3.2% of CD8(+) T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8(+) T cells in the absence of CD25(+) Treg cells (n = 6, P<0.05). Similarly, fewer HBV-specific memory T cells were detected in the presence of these cells (1.3+/-0.4%) in comparison to Treg-depleted mice (2.6+/-0.9%) on d 30 after DNA immunization (n = 6, P<0.01). Both IFN-gamma production and the avidity of the HBV-specific CD8(+) T cell response to antigen were higher in HBV-specific CD8(+) T cells induced in the absence of Treg cells.


CONCLUSIONS
CD25(+) Treg cells suppress priming and/or expansion of antigen-specific CD8(+) T cells during DNA immunization and the peak CD8(+) T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8(+) T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunotherapeutic strategies to control HBV infection by inducing virus-specific cytotoxic T lymphocyte responses in chronically infected subjects.
Furuichi
Yoshihiro
Y
Fourth Department of Internal Medicine (Gastroenterology and Hepatology), Tokyo Medical University, Japan.
Tokuyama
Hirotake
H
Ueha
Satoshi
S
Kurachi
Makoto
M
Moriyasu
Fuminori
F
Kakimi
Kazuhiro
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology*; D004279:DNA, Viral / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000628:therapy*; D007114:Immunization; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000378:metabolism
D004279:DNA, Viral; D017325:Hepatitis B Vaccines; D015375:Receptors, Interleukin-2