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Antigenic Experience Dictates Functional Role of Glycogen Synthase Kinase-3 in Human CD4⁺ T Cell Responses¹

Carlos A. Garcia^*, Manjunatha R. Benakanakere, Pascale Alard^*, Michelle M. Kosiewicz^*, Denis F. Kinane and Michael Martin^2,*,

^* Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292; and Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, KY 40292

Signals induced by the TCR and CD28 costimulatory pathway have been shown to lead to the inactivation of the constitutively active enzyme, glycogen synthase kinase-3 (GSK3), which has been implicated in the regulation of IL-2 and T cell proliferation. However, it is unknown whether GSK3 plays a similar role in naive and memory CD4⁺ T cell responses. Here we demonstrate a divergence in the dependency on the inactivation of GSK3 in the proliferative responses of human naive and memory CD4⁺ T cells. We find that although CD28 costimulation increases the frequency of phospho-GSK3 inactivation in TCR-stimulated naive and memory CD4⁺ T cells, memory cells are less reliant on GSK3 inactivation for their proliferative responses. Rather we find that GSK3β plays a previously unrecognized role in the selective regulation of the IL-10 recall response by human memory CD4⁺ T cells. Furthermore, GSK3β-inactivated memory CD4⁺ T cells acquired the capacity to suppress the bystander proliferation of CD4⁺ T cells in an IL-10-dependent, cell contact-independent manner. Our findings reveal a dichotomy present in the function of GSK3 in distinct human CD4⁺ T cell populations.

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 research was supported by National Institute of Dental Research Grant R01DE017680.

² Address correspondence and reprint requests to Dr. Michael Martin, 501 South Preston Street, University of Louisville School of Dentistry, Room 211A, Louisville, KY 40202. E-mail address: m0mart08{at}louisville.edu

³ Abbreviations used in this paper: GSK3, glycogen synthase kinase-3; 7-AAD, 7-aminoactinomycin D; siRNA, small interfering RNA.

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				C. A. Garcia, H. Wang, M. R. Benakanakere, E. Barrett, D. F. Kinane, and M. Martin c-Jun Controls the Ability of IL-12 to Induce IL-10 Production from Human Memory CD4+ T Cells J. Immunol., October 1, 2009; 183(7): 4475 - 4482. [Abstract] [Full Text] [PDF]