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Dominant Role of Antigen Dose in CD4⁺Foxp3⁺ Regulatory T Cell Induction and Expansion¹

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

The definitions of tolerogenic vs immunogenic dendritic cells (DC) remain controversial. Immature DC have been shown to induce T regulatory cells (Treg) specific for foreign and allogeneic Ags. However, we have previously reported that mature DC (mDC) prevented the onset of autoimmune diabetes, whereas immature DC (iDC) were therapeutically ineffective. In this study, islet-specific CD4⁺ T cells from BDC2.5 TCR-transgenic mice were stimulated in the absence of exogenous cytokine with iDC or mDC pulsed with high- or low-affinity antigenic peptides and examined for Treg induction. Both iDC and mDC presenting low peptide doses induced weak TCR signaling via the Akt/mammalian target of rapamycin (mTOR) pathway, resulting in significant expansion of Foxp3⁺ Treg. Furthermore, unpulsed mDC, but not iDC, also induced Treg. High peptide doses induced strong Akt/mTOR signaling and favored the expansion of Foxp3^neg Th cells. The inverse correlation of Foxp3 and Akt/mTOR signaling was also observed in DO11.10 and OT-II TCR-transgenic T cells and was recapitulated with anti-CD3/CD28 stimulation in the absence of DC. IL-6 production in these cultures correlated positively with Ag dose and inversely with Treg expansion. Studies with T cells or DC from IL-6^–/– mice revealed that IL-6 production by T cells was more important in the inhibition of Treg induction at low Ag doses. These studies indicate that the strength of Akt/mTOR signaling, a critical T cell-intrinsic determinant for Treg vs Th induction, can be controlled by adjusting the dose of antigenic peptide. Furthermore, this operates in a dominant fashion over DC phenotype and cytokine production.

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 American Diabetes Association Grant 1-06-RA-94 (to P.A.M.). M.S.T. is supported by National Institutes of Health Training Grant 5T32 CA82084-10.

² Address correspondence and reprint requests to Dr. Penelope A. Morel, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261. E-mail address: morel{at}pitt.edu

³ Abbreviations used in this paper: NOD, nonobese diabetic; Treg, regulatory T cell; DC, dendritic cell; mTOR, mammalian target of rapamycin; Tg, transgenic; MFI, mean fluorescence intensity; WT, wild type; G4DC, DC grown in GM-CSF+IL4; GMDC, DC grown in G4-CSF clone; pS6, phosphorylated S6 ribosomal protein.

⁴ The online version of this article contains supplemental material.