Induction of anergy in resting human T lymphocytes by immobilized anti-CD3 antibodies.
How the T cell receptor (TcR)/CD3 complex mediates not only the induction of T cell activation but also suppressive effects like T cell anergy or apoptosis is not well understood. Here we describe a series of preincubation and restimulation experiments which demonstrate that primary stimulation of resting, unseparated human T cells with mitogenic doses of immobilized anti-CD3 antibodies induces hyporesponsiveness upon restimulation of the cells. Various costimuli can prevent this type of anergy to a variable degree if present during the preincubation period, phorbol 12-myristate 13-acetate (PMA) being the most and anti-CD4 antibody the least effective. If employed together with anti-CD3 antibody during the restimulation phase of the assay, interleukin (IL)-2, IL-4 and anti-CD28 antibody break anergy almost completely. Proliferation induced by a submitogenic dose of anti-CD3 antibody supplemented by costimulatory signals (anti-CD2, anti-CD4, anti-CD28, IL-2, IL-4 or PMA) does not result in hyporesponsiveness. Taken together, these results support a modified view of the two-signal model for T cell activation according to which anergy induction in resting T cells occurs if primary proliferation is induced by high density triggering of the TcR/CD3 complex in the absence of accessory signals. We discuss possible implications of these findings for the induction of peripheral tolerance.
Wolf
H
H
Labor für Rationale Immuntherapie, Medizinische Klinik III der Universität München, FRG.
Müller
Y
Y
Salmen
S
S
Wilmanns
W
W
Jung
G
G
D000328:Adult; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D016923:Cell Death / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017252:CD3 Complex; D007376:Interleukin-2; D015847:Interleukin-4; D013755:Tetradecanoylphorbol Acetate