CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo.
Treatment with a cocktail of CD4 and CD8-specific monoclonal antibodies (mAb) induces long-term transplantation tolerance and regulatory CD4(+) T cells that induce tolerance in non-tolerant T cells. In contrast, treatment with a CD4-specific mAb alone fails to induce long-term tolerance. The current study was designed to test the hypothesis that CD8 blockade plays a role in promoting the development of CD4(+) regulatory T cells. Using the DO11.10 CD4(+) TCR transgenic mouse model we show that treatment with a CD4/CD8-specific mAb cocktail induces antigen-specific tolerance to OVA, measured by a significant decrease in OVA-specific IgG, on challenge with antigen. Although treatment with OVA and the CD4-specific mAb alone also induces a significant decrease in OVA-specific antibody, the number of DO11.10 cells is significantly greater in mice treated with the CD4/CD8-specific mAb cocktail, and this is associated with a significant increase in proliferation of DO11.10 cells in response to specific antigen. DO11.10 cells sorted from mice made tolerant to OVA with the CD4/CD8-specific mAb cocktail promote an OVA-specific IgG1 (Th2-type) response but not an OVA-specific IgG3 (Th1-type) response on transfer into new syngeneic recipients, suggesting their ability to regulate the type of antigen-specific immune response that ensues after priming with antigen. In addition, DO11.10 cells from tolerant mice express markers that are characteristic of CD4(+) regulatory cells, including FOXP3, GITR and CTLA4, but not CD25. Taken as a whole, these data suggest that CD8 blockade promotes CD4(+) FOXP3(+) regulatory CD4(+) T cells by promoting their proliferation in tolerant mice.
Wang
Z
Z
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Davies
J D
JD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000941:Antigens / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D000941:Antigens; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D010047:Ovalbumin