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Unrestrained Glycogen Synthase Kinase-3 Activity Leads to Activated T Cell Death and Can Be Inhibited by Natural Adjuvant¹

Sadhak Sengupta^*, Padmini Jayaraman^*,, Paula M. Chilton^*, Carolyn R. Casella^* and Thomas C. Mitchell^2,*,

^* Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40202

Activated T cell death (ATCD) after peak clonal expansion is required for effective homeostasis of the immune system. Using a mouse model of T cell clonal expansion and contraction, we found that regulation of the proapoptotic kinase glycogen synthase kinase (GSK)-3 plays a decisive role in determining the extent to which T cells are eliminated after activation. Involvement of GSK-3 in ATCD was tested by measuring T cell survival after GSK-3 inhibition, either ex vivo with chemical and pharmacological inhibitors or in vivo by retroviral expression of a dominant-negative form of GSK-3. We also measured amounts of inactivating phosphorylation of GSK-3 (Ser⁹) in T cells primed in the presence or absence of LPS. Our results show that GSK-3 activity is required for ATCD and that its inhibition promoted T cell survival. Adjuvant treatment in vivo maintained GSK-3 (Ser⁹) phosphorylation in activated T cells, whereas with adjuvant-free stimulation it peaked and then decayed as the cells became susceptible to ATCD. We conclude that the duration of GSK-3 inactivation determines activated T cell survival and that natural adjuvant stimulation decreases the severity of clonal contraction in part by keeping a critical proapoptotic regulatory factor, GSK-3, inactivated.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants AI51377 and AI059023, the Commonwealth of Kentucky Research Challenge Trust Fund, the Kentucky Lung Cancer Research Program, and the Jewish Hospital Foundation.

² Address correspondence and reprint requests to Dr. Thomas C. Mitchell, Institute for Cellular Therapeutics, University of Louisville, Donald Baxter Research Building, 570 South Preston Street, Room 404C, Louisville, KY 40202. E-mail address: tom.mitchell{at}louisville.edu

³ Abbreviations used in this paper: ACTD, activated T cell death; glycogen synthase kinase; Tg, transgenic; pAkt, phosphorylated-Akt; phospho-GSK, phosphorylated GSK; SAg, superantigen; SEA, staphylococcal enterotoxin A; qPCR, quantitative PCR; Fwd, forward; Rev, reverse; CT, cycle threshold.

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