T cell receptor/CD3 and CD28 use distinct intracellular signaling pathways.
Ligation of the T cell membrane antigen CD28 strongly enhances cytokine secretion in human T lymphocytes that are activated via T cell receptor (TcR)/CD3 or CD2 molecules. This study was undertaken to investigate whether, as has been indicated for activation via TcR/CD3, stimulation via CD28 is dependent on the activation of protein kinase C (PKC). Two inhibitors of PKC, 1-alkyl 2-methyl-glycerol and staurosporine, caused a dose-dependent inhibition of T cell proliferation induced by anti-CD3 monoclonal antibodies (mAb). The induction of interleukin (IL) 2 secretion was found to be more sensitive to the effects of the PKC inhibitors than the up-regulation of IL 2 receptor expression. In marked contrast, the anti-CD28 mAb-mediated enhancement of T cell proliferation and IL 2 secretion were insensitive to the action of either compound. We conclude that two independent signaling pathways may be operational in human T cells. The first used by TcR/CD3 depends on the activation of PKC, whereas the second is employed by CD28 and functions independently of PKC.
Van Lier
R A
RA
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service, University of Amsterdam, The Netherlands.
Brouwer
M
M
De Groot
E D
ED
Kramer
I
I
Aarden
L A
LA
Verhoeven
A J
AJ
D000470:Alkaloids / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018106:CD28 Antigens; D017252:CD3 Complex; D006801:Humans; D008213:Lymphocyte Activation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019311:Staurosporine; D013601:T-Lymphocytes / Q000276:immunology*
D000470:Alkaloids; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D011493:Protein Kinase C; D019311:Staurosporine