Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4.
The importance of CD28 costimulation to a primary T cell response in vivo was assessed in an adoptive transfer system where a small population of peptide-specific CD4+ TCR transgenic T cells can be physically tracked. Ag-dependent clonal expansion of the transgenic T cells in draining lymph nodes was blocked by cyclosporin A and required a CD28 signal that was completely inhibited by CTLA-4-Ig or a combination of anti-B7-1 and anti-B7-2 mAbs, but not by either Ab alone. In vivo treatment with the combination of anti-B7-1 and anti-B7-2 mAbs also blocked conversion of the Ag-specific T cells to the activated phenotype. In contrast, anti-CTLA-4 Fab greatly enhanced the in vivo clonal expansion of the Ag-specific T cells. These results suggest that Ag-driven proliferation and phenotype conversion of naive CD4+ T cells is dependent on CD28-derived signals and is inhibited by CTLA-4.
Kearney
E R
ER
Department of Microbiology, University of Minnesota Medical School, Minneapolis 55455, USA.
Walunas
T L
TL
Karr
R W
RW
Morton
P A
PA
Loh
D Y
DY
Bluestone
J A
JA
Jenkins
M K
MK
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069594:Abatacept; D010047:Ovalbumin