Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4+ T cells is regulated by the antigen-presenting cell.
Stimulation of the TCR of activated, mature T cells by an APC produces a spectrum of functional responses. Most of those responses positively promote immunity and inflammation. However, death of the responding T cell, which would limit subsequent inflammation, can also result from such stimulation. We compare the Ag threshold necessary to promote inflammation through cytokine production with the Ag threshold necessary to limit inflammation through T cell death. These two responses are independently regulated by the APC and this regulation is selective for both different APC products and different T cell subsets. The costimulator B7 selectively decreases the Ag threshold for cytokine production in Th1 cells with no effect on the Ag threshold for Th1 death. B7 has no effect on the Th2 Ag threshold for cytokine production or death. In contrast, IFN-gamma negatively modulates a macrophage product that selectively increases the threshold of Ag necessary to stimulate death in Th2 cells, but has no effect on cytokine production by Th2 cells or cytokine production or death of Th1 cells. This selective regulation of cytokine production and T cell death may play an important role in both shaping the quality of a given immune response and in providing a general mechanism for the regulation of the immune response by limiting inflammation and through peripheral deletion of inappropriate T cell specificities.
Wang
R
R
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110.
Murphy
K M
KM
Loh
D Y
DY
Weaver
C
C
Russell
J H
JH
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000941:Antigens / Q000276:immunology*; D000954:Antigens, Surface / Q000032:analysis / Q000235:genetics; D018122:B7-1 Antigen; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004768:Enterotoxins / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010047:Ovalbumin / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000941:Antigens; D000954:Antigens, Surface; D018122:B7-1 Antigen; D017252:CD3 Complex; D016207:Cytokines; D004768:Enterotoxins; D015847:Interleukin-4; C026066:enterotoxin A, Staphylococcal; D010047:Ovalbumin