Regulation of T cell apoptosis via T cell receptors and steroid receptors.
Less than 5% of immature CD4/CD8 double-positive (DP) thymocytes are positively selected to survive and differentiate into single-positive CD4 and CD8 T cells, while self-reactive DP thymocytes undergo apoptosis (negative selection). Both positive and negative selection events are active processes that involve signaling through the T cell receptors (TCRs) and through some accessory molecules. The two events differ quantitatively in the strength of the interaction between TCR and peptide/major histocompatibility complex molecules. We established an in vitro model of positive selection that can be analyzed quantitatively. Positive selection is likely to inhibit glucocorticoid-induced apoptosis in DP thymocytes. Proper crosslinking of TCR together with CD4, CD8, or LFA-1 inhibits the death, and its inhibitory activity is mimicked by proper combinations of ionomycin, a calcium ionophore, and phorbol myristate acetate (PMA), a protein kinase C (PKC) activator. The drug concentrations are within narrow ranges, and are lower than those which are required for the proliferation of mature T cells. Transient stimulation with the combinations of ionomycin and PMA induces differentiation and commitment of isolated DP thymocytes to the CD4 or CD8 T cell lineage in suspension cultures. The level of PKC activity appears to determine the lineage to commit. Functional mature T cells are induced from the committed cells upon secondary stimulation. Activation of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, also appears to be essential for positive selection as well as for the inhibition of glucocorticoid-induced apoptosis. Negative selection and the regulation of mature T cell apoptosis through TCR and steroid receptors are also discussed.
Iwata
M
M
Project Research Center, Mitsubishi Kasei Institute of Life Sciences, Tokyo, Japan.
Ohoka
Y
Y
Kuwata
T
T
Asada
A
A
D000818:Animals; D017209:Apoptosis; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D005938:Glucocorticoids / Q000097:blood; D007211:Indoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011987:Receptors, Steroid / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D016559:Tacrolimus / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
D002148:Calmodulin-Binding Proteins; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007211:Indoles; D007529:Isoflavones; D008301:Maleimides; D011948:Receptors, Antigen, T-Cell; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D015759:Ionomycin; D014212:Tretinoin; D019833:Genistein; D011493:Protein Kinase C; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; C070515:bisindolylmaleimide I; D016559:Tacrolimus