CD8 blockade promotes antigen responsiveness to nontolerizing antigen in tolerant mice by inhibiting apoptosis of CD4+ T cells.
Using the DO11.10 CD4+ TCR-transgenic mouse system, we have recently shown that CD8 blockade promotes the expansion of Ag-specific regulatory CD4+ T cells in mice made tolerant to OVA with anti-CD4 mAb. We now show that CD8 blockade is also critical to promoting responses to nontolerizing Ag in anti-CD4 mAb-treated tolerant mice. Previously published work shows that treatment with anti-CD4 mAb without CD8 blockade induces Ag-specific tolerance. We now show that, in addition to inducing tolerance, anti-CD4 mAb treatment also significantly reduces responsiveness to irrelevant, nontolerizing Ag, and this unresponsiveness is associated with significant apoptosis of the CD4+ T cells. Anti-CD4 mAb-induced apoptosis is inhibited by cotreatment with anti-CD8 mAb and responsiveness to irrelevant Ag is restored, while Ag-specific tolerance is maintained. These data suggest that CD8 blockade promotes responsiveness to nontolerizing Ags in tolerant mice by inhibiting CD4+ T cell apoptosis.
Wang
Zhuangzhi
Z
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Davies
Joanna D
JD
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D017209:Apoptosis / Q000276:immunology*; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis / Q000276:immunology*; D049109:Cell Proliferation; D004338:Drug Combinations; D000939:Epitopes / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007108:Immune Tolerance / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000637:transplantation
D019138:Antibodies, Blocking; D015704:CD4 Antigens; D016827:CD8 Antigens; D004338:Drug Combinations; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010047:Ovalbumin