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CD28 Signaling in T Regulatory Precursors Requires p56^lck and Rafts Integrity to Stabilize the Foxp3 Message¹

Cristina Nazarov-Stoica^*, Jacqueline Surls^*, Constantin Bona, Sofia Casares^*, and Teodor-D. Brumeanu^2,*

^* Department of Medicine, Division of Immunology, Uniformed Services University of Health Sciences, Bethesda, MD 20814; Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029; and Naval Medical Research Center, Infectious Diseases Directorate, Division of Malaria, Silver Spring, MD 20910

Naturally occurring CD4⁺25^highFoxp3⁺ T regulatory (T-reg) cells are critical for maintaining tolerance to self and non-self Ags. The Foxp3 master-regulatory gene and CD28 costimulation are both required for thymic development and suppressogenic function of CD4⁺25^highFoxp3⁺ T-regs. Herein, we show that the sole CD28 stimulation of T-reg thymic precursors augments Foxp3 expression through the increase in Foxp3 mRNA span life by a mechanism involving p56^lck and its binding motif on CD28 cytosolic tail, as well as the lipid rafts. We found that 1) the glycosphingolipids and cholesterol components of lipid rafts were highly expressed and unusually partitioned in T-reg thymic precursors as compared with the conventional T cell precursors, 2) the CD28 receptor density on cell membrane is proportional with the content of cholesterol in lipid rafts and with the level of Foxp3 mRNA expression in T-reg precursors, and 3) the CD28-mediated increase of Foxp3 mRNA span life was paralleled by an increased proliferative and suppressogenic capacity of terminally differentiated CD4⁺25^highFoxp3⁺ T-reg precursors. Thus, the functional integrity of CD28 receptor p56^lck and plasma membrane lipid rafts are all prerequisites for up-regulation and long-term expression of Foxp3 mRNA transcripts in CD4⁺25^highFoxp3⁺ T-reg precursors.

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 study was supported by grants from the National Institutes of Health, DK61927 and DK61326 (to T.-D.B.) and DK077521 (to S.C.), and JDRF-12002-1151 (to S.C. and T.-D.B.).

² Address correspondence and reprint requests to Dr. Teodor-D. Brumeanu, Uniformed Services University of Health Sciences, Department of Medicine, Division of Immunology, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address: tbrumeanu{at}usuhs.mil

³ Abbreviations used in this paper: T-reg, T regulatory cell; ARE, adenosine-rich elements (AAA); CTX-B, cholera toxin B subunit; DRB, 5,6-dichloro-1-β-D-ribofuranosyl-benzimide-azole; β-MCD, methyl-β-cyclodextrin; MFI, mean fluorescence intensity; TcH, T cell hybridoma; wt, wild type; 3'-UTR, the 3 end of mRNA untranslated region; HuR, human Ag; TTP, tristetraproline; siRNA, short interference soluble RNA; KO, knockout; DN, double negative; LDLR, low density lipoprotein receptor.