title: CD4(+)CD25(+) T-cells control autoimmunity in the absence of B-cells.
abstract: OBJECTIVE
  Tumor necrosis factor ligand family members B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) can exert powerful effects on B-cell activation and development, type 1 T-helper cell (Th1) immune responses, and autoimmunity. We examined the effect of blocking BAFF and APRIL on the development of autoimmune diabetes.
  
  
  METHODS
  Female NOD mice were administered B-cell maturation antigen (BCMA)-Fc from 9 to 15 weeks of age. Diabetes incidence, islet pathology, and T- and B-cell populations were examined.
  
  
  RESULTS
  BCMA-Fc treatment reduced the severity of insulitis and prevented diabetes development in NOD mice. BCMA-Fc-treated mice showed reduced follicular, marginal-zone, and T2MZ B-cells. B-cell reduction was accompanied by decreased frequencies of pathogenic CD4(+)CD40(+) T-cells and reduced Th1 cytokines IL-7, IL-15, and IL-17. Thus, T-cell activation was blunted with reduced B-cells. However, BCMA-Fc-treated mice still harbored detectable diabetogenic T-cells, suggesting that regulatory mechanisms contributed to diabetes prevention. Indeed, BCMA-Fc-treated mice accumulated increased CD4(+)CD25(+) regulatory T-cells (Tregs) with age. CD4(+)CD25(+) cells were essential for maintaining euglycemia because their depletion abrogated BCMA-Fc-mediated protection. BCMA-Fc did not directly affect Treg homeostasis given that CD4(+)CD25(+)Foxp3(+) T-cells did not express TACI or BR3 receptors and that CD4(+)CD25(+)Foxp3(+) T-cell frequencies were equivalent in wild-type, BAFF(-/-), TACI(-/-), BCMA(-/-), and BR3(-/-) mice. Rather, B-cell depletion resulted in CD4(+)CD25(+) T-cell-mediated protection from diabetes because anti-CD25 monoclonal antibody treatment precipitated diabetes in both diabetes-resistant NOD.microMT(-/-) and BCMA-Fc-treated mice.
  
  
  CONCLUSIONS
  BAFF/APRIL blockade prevents diabetes. BCMA-Fc reduces B-cells, subsequently blunting autoimmune activity and allowing endogenous regulatory mechanisms to preserve a prehyperglycemic state.
authors.affiliation: Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: Eliana
authors.initials: E
authors.lastname: Mariño
authors.forename: Jeanette
authors.initials: J
authors.lastname: Villanueva
authors.forename: Stacey
authors.initials: S
authors.lastname: Walters
authors.forename: David
authors.initials: D
authors.lastname: Liuwantara
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey