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Analysis of Adhesion Molecules, Target Cells, and Role of IL-2 in Human FOXP3⁺ Regulatory T Cell Suppressor Function¹

Dat Q. Tran^*, Deborah D. Glass^*, Gulbu Uzel, Dirk A. Darnell, Christine Spalding, Steven M. Holland and Ethan M. Shevach^2,*

^* Laboratory of Immunology and Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

FOXP3⁺ regulatory T cells (Tregs) are central to the maintenance of self-tolerance and immune homeostasis. The mechanisms of action and cellular targets for Treg-mediated suppression remain controversial. The critical adhesion molecules utilized by Tregs for the interaction with their target cells have not been well characterized. We show that human CD4⁺FOXP3⁺CD25^high cells (hTregs) suppress the activation of mouse responders as efficiently as mouse Tregs. LFA-1 (CD11a/CD18) on the hTregs is critical for their suppressor function, since suppression can be reversed with blocking anti-hCD11a or anti-hCD18 mAb. Tregs from patients with LFA-1 deficiency fail to suppress human and mouse responders. Mouse CD4⁺ T cells deficient in ICAM-1 can be suppressed by hTregs, indicating that the hTregs target mouse dendritic cells (DCs) through the binding of human LFA-1 to mouse ICAM-1. Coculture of mouse DCs with hTregs, but not hTregs from LFA-1-deficient patients, prevented the up-regulation of CD80/CD86 on the DCs and their capacity to activate responder T cells. Lastly, IL-2 is not required for hTreg suppressor function under optimal stimulatory condition and IL-2 consumption plays no role in hTreg-mediated suppression. Taken together, one of the mechanisms of Treg-mediated suppression functions across species and mediates an LFA-1/ICAM-1-dependent interaction between Tregs and DCs.

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 funded by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

² Address correspondence and reprint requests to Dr. Ethan M. Shevach, Laboratory of Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 10 Center Drive, Building 10, Room 11N315, Bethesda, MD 20892. E-mail address: eshevach{at}niaid.nih.gov

³ Abbreviations used in this paper: Treg, regulatory T cell; h, human; m, mouse; DC, dendritic cell; HA, hemagglutinin; Tg, transgenic; rh, recombinant human; LAP, latency-associated peptide; LAD-1, leukocyte adhesion deficiency type 1.

⁴ The online version of this article contains supplemental material.

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