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Original Article

^a Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, London, Ontario N6G 2V4, Canada
^b Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada
^c Department of Medicine, University of Western Ontario, London, Ontario N6A 5C1, Canada
^d Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada
Director, Autoimmunity/Diabetes Group, The John P. Robarts Research Institute, 1400 Western Rd., London, Ontario N6G 2V4, Canada.519-663-3847519-663-3972

del{at}rri.on.ca

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH₂-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.

Key Words: Fas ligand • apoptosis • p38 MAPK • JNK • T cells

Abbreviations used in this study: AICD, activation-induced cell death; ATF-2, activating transcription factor 2; DN, dominant negative; ERK, extracellular signal–regulated kinase; FADD, Fas-associated death domain; FasL, Fas ligand; GST, glutathione-S-transferase; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PI, propidium iodide; SAPK, stress-activated protein kinase; WT, wild-type.

© 2000 The Rockefeller University Press

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