The Role of Foxo3 in B Cell Tolerance

B cells secrete antibodies in order to help defend the body against pathogens. Due to the enormous diversity of B cell receptors required to recognize pathogens, some self-reactive receptors are generated. It is important for the immune system to prevent autoimmune cells from attacking one's self. This can be done at the immature B cell stage through receptor editing, deletion of the B cell, or anergy (inactivation) of the B cell. During editing, the receptor recombines its components in order to generate a new receptor, which is tested for auto-reactivity. If the receptor is strongly auto-reactive after editing, the cell dies by apoptosis. Foxo3 is a transcription factor that participates in pro-apoptotic pathways in several cell types. Previous work in our lab showed that apoptosis is reduced in immature B cells from Foxo3-/- mice, and others have observed decreased levels of Foxo3 in B cells from mouse models of lupus (an autoimmune disease in which B cells produce antibodies reactive against the body's own DNA). It is hypothesized that edited cells that remain auto-reactive may survive inappropriately in the absence of Foxo3. B cells that have undergone receptor editing are more likely to express the Igλ light chain and to have undergone a process called "RS recombination." Foxo3-/- mice were found by flow cytometry to exhibit increased Igλ+ B cells in the immature B cells of the bone marrow, as well as in the transitional B cells of the spleen. PCR demonstrated increased RS recombination in Igλ+ B cells from Foxo3-/- mice compared to wild-type mice. Anti-double-stranded DNA ELISAs were run on supernatants from total B cells stimulated by LPS to secrete antibodies. These showed no difference in auto-reactivity between wild-type mice and Foxo3-/- mice. Thus, there appears to be an increase in receptor editing in the knockout mice, but not an overall increase in the auto-reactivity of the total population of B cells. This suggests that the reduced apoptosis of Foxo3-/- immature B cells allows cells that were originally auto-reactive a longer window of time in which to edit their receptors away from auto-reactivity.