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Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival¹

Boris P.-L. Lee^*,, Elaine Mansfield, Szu-Chuan Hsieh, Tina Hernandez-Boussard^¶, Wenhao Chen^*,, Christopher W. Thomson^*,, Megan S. Ford^*,, Steven E. Bosinger^*, Sandy Der, Zhu-xu Zhang^*,, Meixia Zhang, David J. Kelvin^*,¶, Minnie M. Sarwal^2, and Li Zhang^2,3,*,,

^* Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Toronto, Ontario, Canada; and Departments of Pediatrics and ^¶ Genetics, Stanford University, Stanford, CA 94305

Recent studies have demonstrated that both mouse and human TCR⁺CD3⁺NK1.1^–CD4^–CD8^– double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8⁺ and CD4⁺ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8⁺ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 ± 11.1 days) compared with untreated controls (22.8 ± 10.5 days; p < 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q < 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including FcRI subunit and CXCR5, which are >50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival.

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