TNFαRII expressing FoxP3+ T reg cells have a reversible defect in their ability to suppress the autoimmune disease thyrocyte epithelial cell hyperplasia/proliferation (115.17)

Abstract

Most IFN-γ-/- NOD.H-2h4 mice given 0.05% NaI in their water develop an autoimmune thyroid disease characterized by infiltrating lymphocytes, expression of TNFα and TGFβ, production of anti-thyroglobulin antibodies, and uncontrolled proliferation of TEC, resulting in destruction of the gland and loss of function. IFN-γ-/- NOD.H-2h4 mice have elevated FoxP3+ CD4+ T reg in cervical LN and spleen (25-40%, and 25-35% of CD4+ T cells) dependent on age, presence of severe disease, and absence of IFN-γ. T reg cells from mice with severe TEC H/P exhibit a suppressive phenotype with expression of high levels of FoxP3, CD25, and TNFαRII (p75), and they suppress anti-CD3 mediated proliferation of T cells in vitro. Splenocytes from mice with severe TEC H/P transfer severe TEC H/P to IFN-γ-/- SCID recipients following 72 hr culture. During culture, percentages of T reg decrease, allowing transfer of severe TEC H/P. However, in recipient mice, percentages of T reg increase, and despite increased numbers of T reg in LN and spleen, the mice develop severe TEC H/P. This data suggests there may be a defect in the ability of these T reg to suppress TEC H/P, either because of an intrinsic defect in the T reg or because effector cells are resistant to suppression. The defect is reversible as addition of IL-2 (100 U/ml) to the culture increases T reg percentages, and inhibits transfer of TEC H/P, restoring the ability of T reg to suppress TEC H/P in recipient SCID mice.