Failed down-regulation of PI3K signaling makes autoreactive B cells receptive to bystander T cell help.

Phosphatase suppression of PI3K signaling is an important mechanism by which peripheral autoreactive B cells are kept in an unresponsive/anergic state. Loss of this suppression, due to genetic alleles that confer risk of autoimmunity, often occurs in autoreactive B cells of individuals who develop autoimmune disease. Here we demonstrate that de-repression of PI3K signaling promotes autoantibody responses of a DNA-reactive B cell clone by relaxing dependence of autoantibody responses on T cell-derived helper signals. These results suggest that impaired regulation of PI3K signaling can promote autoantibody responses in two ways: by restoring antigen receptor signaling and by enabling autoreactive B cells to circumvent restrictions imposed by T cell tolerance mechanisms.