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Cutting Edge: Responder T Cells Regulate Human DR⁺ Effector Regulatory T Cell Activity via Granzyme B¹

Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115

MHC class II expression identifies an effector subset of human CD4⁺CD25^highFoxP3^high natural regulatory T cells (DR⁺ Tregs) that induces more rapid suppression and exhibits higher FoxP3 expression than the remaining Treg population. Although Tregs are known to be highly sensitive to apoptosis, in this study we demonstrate that this sensitivity is primarily a feature of DR⁺ Tregs. Granzyme B (GzmB) is strongly expressed by nonregulatory responder CD4 T cells, whereas effector DR⁺ Tregs express little GzmB. Strong TCR stimulation markedly increases the expression of GzmB in all dividing responder CD4 T cells and mitigates the suppression by DR⁺ Tregs. DR⁺ Treg suppressive activity reemerges if GzmB is neutralized. We show that responder cells actively kill effector Tregs by producing GzmB in response to strong TCR stimulation. Thus, the production of GzmB by strongly activated CD4 T cells represents a mechanism by which CD4 T cells resist Treg suppression.

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 National Institutes of Health Grants NS24242, U01 DK6192601, R01 NS2424710, P01 AI39671, and P01 NS38037, by National Multiple Sclerosis Society Grants RG3825A1, RG2172C9, and RG3308A10, by the 2004 Federation of Clinical Immunology Societies Centers of Excellence Amgen Award, and by the 2007 Dana Scholars Award.

² Address correspondence and reprint requests to Dr. Clare Baecher-Allan, 77 Avenue Louis Pasteur, Harvard Medical School, Boston, MA. E-mail address: callan{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; FasL, Fas ligand; GzmA, granzyme A; GzmB, granzyme B; siRNA, small interfering RNA; Tresp, responder T cell.

⁴ The online version of this article contains supplemental material.