Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/07/16/jimmunol.100013

The importance of regulatory T cells in immune tolerance is illustrated by the human immune dysregulatory disorder IPEX (immune dysregulation, polyendocrinopathy, enteropathy, Xlinked), caused by a lack of regulatory T cells due to decreased or absent expression of Foxp3. Although the majority of work on regulatory T cells has focused on their ability to suppress T cell responses, the development of significant autoantibody titers in patients with IPEX suggests regulatory T cells also contribute to the suppression of autoreactive B cells. Although these observations suggest that regulatory T cells have an important role in B cell biology, no studies have directly determined whether an absence of regulatory T cells impacts B cell development or B cell tolerance. Using a murine model of IPEX, harboring a mutation in the Foxp3 gene derived from a human IPEX patient, we show that B cell development is significantly altered in the absence of regulatory T cells. Furthermore, we identify a loss of B cell anergy as a likely mechanism to explain the production of autoantibodies and loss of tolerance that occurs in the absence of regulatory T cells. Our results suggest that regulatory T cells, by either direct, or indirect mechanisms, modulate B cell development and anergy.

Regulatory T cells (Tregs) are crucial for the maintenance of immune tolerance and the absence of Tregs results in significant autoantibody production. This suggests that Tregs play a key role in B cell tolerance. The mechanism by which Tregs regulate B cell tolerance has yet to be resolved but has important implications for our understanding of autoimmunity. Using both constitutive and inducible models, we show that the absence of Tregs results in autoantibody production, due to the loss of B cell anergy. Further studies show that this is dependent on the presence of helper T cells. We propose that the absence of Tregs results in the dysregulation of helper T cells that drive the loss of B cell anergy. Interestingly, our studies show the expansion of a CD4+GL7+ population in the absence of Tregs. Subsequent analysis shows that many of these cells express CXCR5 and thus resemble germinal-center TFH cells, an observation confirmed by their expression of Bcl6 and IL-21. We hypothesize that the absence of Tregs drives the expansion of TFH cells that play a role in the loss of B cell anergy. Characterization of this proposed mechanism may unveil new strategies for the treatment or prevention of autoantibody-mediated autoimmune diseases.