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CD4⁺CD25^int T Cells in Inflammatory Diseases Refractory to Treatment with Glucocorticoids¹

Richard W. J. Lee^*, Thomas J. Creed^,, Lauren P. Schewitz^*, Paul V. Newcomb, Lindsay B. Nicholson^*,, Andrew D. Dick^2,*, and Colin M. Dayan

^* Academic Unit of Ophthalmology, Department of Clinical Science at South Bristol, University of Bristol; Department of Gastroenterology, United Bristol Healthcare Trust; Department of Cellular and Molecular Medicine, University of Bristol; and Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Department of Clinical Science at South Bristol, University of Bristol, United Kingdom

Up to 30% of patients with autoimmune, allergic, and lymphoproliferative diseases are refractory to glucocorticoid therapy. The present study was undertaken to investigate whether such steroid resistance (SR) is limited to a subpopulation of CD4⁺ T cells and, as IL-2 is a putative driver of SR, whether T cell SR is associated with CD25 expression. We show that SR patients have a characteristic subgroup of activated CD4⁺ T cells that continue to proliferate despite exposure to high-dose Dexamethasone (Dex), demonstrate that CD4⁺CD25^– cells are exquisitely sensitive to Dex whereas CD4⁺CD25^int cells are highly SR, and further find that the combination of an anti-CD25 mAb with Dex enhances suppression of T cell proliferation compared with each agent alone. We therefore conclude that SR is not a general property of all lymphocytes but resides in T cell subpopulations, which are prevalent in SR patients and express intermediary levels of CD25. As a result, we propose a new paradigm for SR disease in which glucocorticoid therapy positively selects SR cells, generating a population of drug-resistant lymphocytes that perpetuate on-going inflammation.

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 Grants RJ4740 and RJ4750 (to R.W.J.L. and A.D.D.) from the National Eye Research Centre. R.W.J.L.’s research fellowship has been jointly funded by the National Eye Research Centre and Astellas Pharma.

² Address correspondence and reprint requests to Prof. Andrew Dick, Bristol Eye Hospital, Lower Maudlin Street, Bristol, BS1 2LX, U.K. E-mail address: a.dick{at}bristol.ac.uk

³ Abbreviations used in this paper: GC, glucocorticoid; SR, steroid resistant; GR, glucocorticoid receptor; SS, steroid sensitive; Dex, dexamethasone; UC, ulcerative colitis; Treg, T regulatory cell; NV, normal volunteer; Bas, basiliximab; 7-AAD, 7-aminoactinomycin; 5-ASA, 5-aminosalicylic acid; int, intermediate.