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Superantigen-Activated Regulatory T Cells Inhibit the Migration of Innate Immune Cells and the Differentiation of Naive T Cells¹

Medical Research Council Centre for Transplantation, King’s College London, School of Medicine, Guy’s Hospital, London, United Kingdom

Regulatory T cells can be used as tools to suppress pathogenic T cells in autoimmunity, graft-vs-host-disease, and transplantation. But even when high numbers of Ag-specific regulatory T cells are available, it is still possible under certain in vivo and in vitro conditions for effector T cells to escape effective control. Current reports suggest that the degree of suppression is modulated by the inflammatory milieu, which can induce resistance to suppression in effector T cells or subvert the inhibitory function of the regulatory T cells. Cells of the innate immune system integrate early signals of injury and infection and have a major impact on the ensuing inflammation. Hence, the modification of these initial events can be key to allowing suppression to dominate. The approach we took here was to test whether the in vivo preactivation of endogenous regulatory T cells with a superantigen could enhance their suppressive potency. We provide evidence that this not only proved effective in expanding the pool of preactivated regulatory T cells but also in preventing the migration of NK cells and granulocytes upon sensitization with matured dendritic cells. The attenuation of innate immune activation was accompanied by linked suppression of adoptively transferred OVA-specific T cells when APC coexpressing OVA and the superantigen were injected. These data suggest that the preactivation of regulatory T cells is a promising approach to increase their potency.

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 British Heart Foundation. Y.T. was supported by the Deutsche Forschungsgemeinschaft (Ta 436-1/1) and A.M.-F. by the Swiss National Science Foundation.

² Current address: Renal Division, University Hospital Freiburg, Freiburg, Germany.

³ G.L and R.L. contributed equally to this work.

⁴ Address correspondence and reprint requests to Dr. Robert Lechler, Medical Research Council Centre for Transplantation, King’s College London, School of Medicine, Guy’s Hospital, Hodgkin Building, London SE1 9RT, United Kingdom. E-mail address: robert.lechler{at}kcl.ac.uk

⁵ Abbreviations used in this paper: Mls, minor lymphocyte stimulating; CD62L, L-selectin; DC, dendritic cell; LN, lymph node; MMTV, mouse mammary tumor virus; NIMA noninherited maternal Ag.