Intracellular signaling events during positive and negative selection of CD4+CD8+ thymocytes in vitro.
We have used in vitro models of thymocyte positive and negative selection in conjunction with selective inhibitors of the TCR-mediated signaling cascade to investigate the intracellular signaling events that mediate these processes. We report that Ro 31.8425, a potent and selective inhibitor of protein kinase C, which blocks the activation of mature T cells in a dose-dependent fashion, has no effect on either positive or negative selection of CD4+8+ thymocytes. In contrast, cyclosporin A fails to prevent negative selection, but inhibits positive selection through a direct effect on developing thymocytes, rather than through the perturbation of stromal cell support. Thus, our data suggest that positive and negative selection may operate via distinct intracellular signaling pathways.
Anderson
G
G
Department of Anatomy, Medical School, University of Birmingham, Edgbaston, United Kingdom.
Anderson
K L
KL
Conroy
L A
LA
Hallam
T J
TJ
Moore
N C
NC
Owen
J J
JJ
Jenkinson
E J
EJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D008213:Lymphocyte Activation; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology*
D004768:Enterotoxins; D007211:Indoles; D007376:Interleukin-2; D008301:Maleimides; D011948:Receptors, Antigen, T-Cell; C071924:Ro 31-8425; D015847:Interleukin-4; C031818:enterotoxin B, staphylococcal; D016572:Cyclosporine; D011493:Protein Kinase C