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In Vitro Expansion Improves In Vivo Regulation by CD4⁺CD25⁺ Regulatory T Cells¹

Jian-Guo Chai^2,*, David Coe^*, Daxin Chen, Elizabeth Simpson, Julian Dyson and Diane Scott

^* Cancer Immunotherapy Group, Transplant Inflammation Group, and Transplantation Biology Group, Department of Immunology, Imperial College London, London, United Kingdom

CD4⁺CD25⁺ T regulatory cells (Tregs) can actively suppress immune responses and thus have substantial therapeutical potential. Clinical application is, however, frustrated by their scarcity, anergic status, and lack of defined specificity. We found that a single injection of a small number of expanded but not fresh HY-specific Tregs protected syngeneic male skin grafts from rejection by immune-competent recipients. The expanded Tregs were predominantly located in the grafts and graft-draining lymph nodes. In vitro expanded Tregs displayed a phenotype of CD25^highCD4^lowFoxp3⁺CTLA4⁺, and also up-regulated IL10 and TGFβ while down-regulating IFN-, GM-CSF, IL5, and TNF- production. Furthermore, expanded Tregs appeared to express a reduced level of Foxp3, which could be prevented by adding TGFβ to the culture, and they also tended to lose Foxp3 following the repeated stimulation. Finally, a proportion of expanded HY-specific Tregs secreted IL2 in response to their cognate peptide, and this finding could be confirmed using Tregs from Foxp3^GFP reporter mice. We not only demonstrated that expanded Tregs are superior to fresh Tregs in suppressing T cell responses against alloantigens, but also revealed some novel immunobiological properties of expended Tregs which are very instructive for modifying current Treg expansion procedures.

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 grants from Cancer Research U.K. (C11356/ A4033/A6994).

² Address correspondence and reprint requests to Dr. J.-G. Chai, Transplantation Biology Group, Department of Immunology, Imperial College London, Hammersmith Campus, London W12 0NN, U.K. E-mail address: jianguo.chai{at}csc.mrc.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; GVHD, graft-vs host disease; BMDC, bone marrow-derived dendritic cell; WT, wild type; LN, lymph node; DC, dendritic cell; MFI, mean fluorescence intensity.

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