Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can regulate dendritic cell-induced activation and cytotoxicity of CD8(+) T cells independently of CD4(+) T cell help.
The mechanisms that regulate the strength and duration of CD8(+) cytotoxic T cell activity determine the effectiveness of an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8(+) T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8(+) T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti-CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8(+) T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4(+) T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8(+) T cells, indicating its potential for tumor immunotherapy even in situations in which CD4(+) T cell help is limited or absent.
McCoy
K D
KD
Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand.
Hermans
I F
IF
Fraser
J H
JH
Le Gros
G
G
Ronchese
F
F
D000069594:Abatacept; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D000956:Antigens, Viral / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007114:Immunization; D018796:Immunoconjugates; D008213:Lymphocyte Activation / Q000187:drug effects*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000956:Antigens, Viral; D018122:B7-1 Antigen; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; D000069594:Abatacept