W88 - IL-21 is a Key Regulator of Chronic Germinal Centers in Autoimmune Settings

Abundant experimental evidence has linked defective B cell and T cell interactions with the development of autoimmunity, highlighting the importance of further investigations into pathways underpinning B cell and T cell collaboration in health and disease.

Elevated levels of the archetypal follicular helper T-cell cytokine interleukin 21 (IL-21) have been reported in many autoimmune conditions including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus, and IL-21 has been widely shown to promote pathology in their corresponding animal disease models. However, the underlying mechanisms of IL-21-dependent regulation of humoral immunity as well as their contribution to the development of autoimmunity remain poorly understood.

Previous work by our group has demonstrated that, alongside systemic autoimmunity, mice rendered deficient for T-cell peripheral regulator CTLA-4 present with a significant upregulation of IL-21 as well as a formation of exacerbated germinal centers (GC). We have taken advantage of this model to home in on the role of IL-21 in the regulation of chronic GC responses in autoimmune settings. By studying GC in CTLA-4-/- mice that were crossed to IL-21R-/- animals we were able to demonstrate that IL-21 represents a key regulator of light zone GC B cell selection and that IL-21 signaling is essential for an efficient formation of the GC dark zone compartment.

Our study provides novel insights into IL-21 involvement in the regulation of GC processes that are central to the development of robust humoral immunity but that may also aid disease pathogenesis in the context of autoimmunity.