Induction of apoptosis by anti-CD3 epsilon F(ab')2 in antigen receptor transgenic murine T cells activated by specific peptide.
Peripheral T cell tolerance can be achieved through deletion of mature CD4+ cells activated by high dose Ag. We tested whether apoptosis of peripheral CD4+ cells could be induced by a stimulatory dose of Ag plus a soluble ligand to the nonpolymorphic epsilon-chain of the TCR-associated CD3 complex. CD4+ T cells from the DO10 mouse express a transgenic TCR-alphabeta specific for OVA peptide 323-339 presented by I-A(d). OVA alone induced clonal activation and expansion of peripheral CD4+/TCR transgene+ cells. Simultaneous exposure to specific Ag plus soluble anti-CD3 Fos, a nonmitogenic anti-CD3epsilon genetically engineered F(ab')2-like Ab, blocked expansion and induced death of CD4+/TCR transgene+ cells, but not CD4+/TCR transgene- T cells. In contrast, a mitogenic anti-CD3epsilon Ab induced polyclonal activation and nonselective T cell death. Sequential stimulation by Ag followed by anti-CD3 Fos also induced death of TCR transgene+ cells, whereas stimulation by anti-CD3 Fos followed by Ag did not affect cell viability or function. Anti-CD3 Fos-induced death was associated with DNA fragmentation characteristic of apoptosis, was facilitated by IL-2, and was initiated by stimulation during the S-G2 phases of the cell cycle. Anti-CD3 Fos could induce deletion of Ag-activated T cells by apoptosis in vivo. Thus, a soluble, non-Fc-binding anti-CD3 Ab can induce programmed cell death of Ag-activated peripheral CD4+ T cells by CD3epsilon cross-linking during S or G2. Peripheral T cell deletion by activation-driven apoptosis is under cell cycle control and can be exploited to achieve selective immunosuppression by nonmitogenic anti-CD3epsilon Abs.
Yu
X Z
XZ
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Zhu
L
L
Davis
J E
JE
Tso
J Y
JY
Hansen
J A
JA
Anasetti
C
C
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology; D000941:Antigens / Q000008:administration & dosage / Q000235:genetics; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000378:metabolism*; D002453:Cell Cycle; D053938:DNA Fragmentation; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015202:Protein Engineering; D016760:Proto-Oncogene Proteins c-fos / Q000008:administration & dosage / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000941:Antigens; D017252:CD3 Complex; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D016693:Receptors, Antigen, T-Cell, alpha-beta; D010047:Ovalbumin