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The Type and Frequency of Immunoregulatory CD4⁺ T-Cells Govern the Efficacy of Antigen-Specific Immunotherapy in Nonobese Diabetic Mice

¹ Curriculum in Oral Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
² Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Address correspondence and reprint requests to Roland Tisch, PhD, Department of Microbiology and Immunology, Mary Ellen Jones Bldg., Room 804, Campus Box no. 7290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7290. E-mail: rmtisch{at}med.unc.edu

Abbreviations: GAD65, glutamic acid decarboxylase 65; HEL, hen egg lysozyme; IL, interleukin; IFN, interferon; pDNA, plasmid DNA; PLN, pancreatic lymph node; RLN, renal lymph node; Treg, regulatory T-cell; TGF, transforming growth factor

Antigen-specific immunotherapy, an approach to selectively block autoimmune diabetes, generally declines in nonobese diabetic (NOD) mice as disease progresses. To define the parameters influencing the efficacy of antigen-specific immunotherapy once diabetes is established, plasmid DNA (pDNA) vaccination was used to suppress autoimmune-mediated destruction of syngeneic islet grafts in diabetic NOD recipients. pDNAs encoding a glutamic acid decarboxylase 65 (GAD65)-Ig molecule (pGAD65), interleukin (IL)-4 (pIL4), and IL-10 (pIL10) significantly delayed the onset of recurrent diabetes compared with pGAD65+pIL10-vaccinated recipients. Despite differences in efficacy, a similar frequency of GAD65-specific CD4⁺ T-cells secreting IL-4, IL-10, or interferon- were detected in mice treated with pGAD65+pIL4+pIL10 and pGAD65+pIL10. However, the frequency of FoxP3-expressing CD4⁺CD25⁺CD62L^hi T-cells was increased in the renal and pancreatic lymph nodes of diabetic recipients vaccinated with pGAD65+pIL4+pIL10. These immunoregulatory CD4⁺CD25⁺ T-cells (CD4⁺CD25⁺ Treg) exhibited enhanced in vivo and in vitro suppressor activity that partially was transforming growth factor-ß dependent. Furthermore, duration of islet graft protection in pGAD65+pIL4+pIL10-vaccinated diabetic recipients correlated with the persistence of CD4⁺CD25⁺ Treg. These data demonstrate that the frequency and maintenance of FoxP3-expressing CD4⁺CD25⁺ Treg influence antigen-induced suppression of ongoing ß-cell autoimmunity in diabetic recipients.

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