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Protection against Autoimmunity in Nonlymphopenic Hosts by CD4⁺CD25⁺ Regulatory T Cells Is Antigen-Specific and Requires IL-10 and TGF-¹

Departments of Medicine and Immunology, Duke University Medical Center, Durham, NC 27710

CD4⁺CD25⁺ regulatory T cells (T_Reg) play a critical role in the control of autoimmunity. However, little is known about how T_Reg suppress self-reactive T cells in vivo, thus limiting the development of T_Reg-based therapy for treating autoimmune diseases. This is in large part due to the dependency on a state of lymphopenia to demonstrate T_Reg-mediated suppression in vivo and the unknown Ag specificity of T_Reg in most experimental models. Using a nonlymphopenic model of autoimmune pneumonitis and T_Reg with known Ag specificity, in this study we demonstrated that these T_Reg can actively suppress activation of self-reactive T cells and protect mice from fatal autoimmune pneumonitis. The protection required T_Reg with the same Ag specificity as the self-reactive T cells and depended on IL-10 and TGF-. These results suggest that suppression of autoimmunity by T_Reg in vivo consists of multiple layers of regulation and advocate for a strategy involving Ag-specific T_Reg for treating organ-specific autoimmunity, because they do not cause generalized immune suppression.

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