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Regulation of T Cell Apoptosis via T Cell Receptors and Steroid Receptors

Project Research Center, Mitsubishi Kasaei Institute of Life Sciences, Minamiooya, Machida-shi, Tokyo, Japan

Key Words. Apoptosis • T cell • Thymocyte • Positive selection • Glucocorticoid • Protein kinase C • Calcineurin • Retinoic acid

Dr. Makoto Iwata, Project Research Center, Mitsubishi Kasei Institute of Life Sciences 11, Minamiooya, Machida-shi, Tokyo, 194 Japan.

Less than 5% of immature CD4/CD8 double-positive (DP) thymocytes are positively selected to survive and differentiate into singlepositive 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, CD9, 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 cells apoptosis through TCR and steroid receptors are also discussed.

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