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Enhanced Engagement of CTLA-4 Induces Antigen-Specific CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^– TGF-1⁺ Adaptive Regulatory T Cells¹

Ruobing Li^*, Nicolas Perez^*, Subha Karumuthil-Melethil^*, Bellur S. Prabhakar, Mark J. Holterman^* and Chenthamarakshan Vasu^*,2

^* Department of Surgery and Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612

CTLA-4 is a critical negative regulator of T cell response and is instrumental in maintaining immunological tolerance. In this article, we report that enhanced selective engagement of CTLA-4 on T cells by Ag-presenting dendritic cells resulted in the induction of Ag-specific CD4⁺CD25⁺Foxp3⁺ and CD4⁺CD25^–TGF-1⁺ adaptive Tregs. These cells were CD62L^low and hyporesponsive to stimulation with cognate Ag but demonstrated a superior ability to suppress Ag-specific effector T cell response compared with their CD62L^high counterparts. Importantly, treatment of mice with autoimmune thyroiditis using mouse thyroglobulin (mTg)-pulsed anti-CTLA-4 agonistic Ab-coated DCs, which results in a dominant engagement of CTLA-4 upon self-Ag presentation, not only suppressed thyroiditis but also prevented reemergence of the disease upon rechallenge with mTg. Further, the disease suppression was associated with significantly reduced mTg-specific T cell and Ab responses. Collectively, our results showed an important role for selective CTLA-4 signaling in the induction of adaptive Tregs and suggested that approaches that allow dominant CTLA-4 engagement concomitant with Ag-specific TCR ligation can be used for targeted therapy.

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 the National Institutes of Health Grant R21 A1059745 and Juvenile Diabetes Research Foundation Regular Grant 1-2005-27.

² Address correspondence and reprint requests to Dr. Chenthamarakshan Vasu, Department of Surgery, University of Illinois at Chicago, 909 South Wolcott, College of Medicine Research Building, Room 7113, M/C790, Chicago, Illinois 60612. E-mail address: chenta{at}uic.edu

³ Abbreviations used in this paper: DC, dendritic cell; BiAb, bispecific antibody; BM, bone marrow; BMDC, BM-derived DC; Foxp3, foxhead box p3 transcription factor; GITR, glucocorticoid-induced tumor necrosis factor receptor; HEL, hen egg lysozyme; LN, lymph node; MFI, mean fluorescence intensity; mTg, mouse thyroglobulin; Treg, regulatory T cell.

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