Fig. 1.

The role of Itch to regulate T cell-B cell interactions and antibody production. Itch deficient patients with autoimmunity and mice lacking Itch develop abnormal serum antibodies. Itch limits levels of spontaneously produced IgM, IgG, and autoantibody, but Itch activity in T cells promotes virus-specific IgG production. A) Itch negatively regulates serum IgM levels through suppressing IL-4 production by T cells. The source of IgM is thought to be B1-B cells, suggesting that these T-B interactions are extrafollicular. B) Mice lacking Itch only in T cells mount defective antibody responses to viral infection. Itch promoted Tfh differentiation and germinal center responses by ubiquitylation and degradation of Foxo1, allowing protein expression of the Tfh master regulator, Bcl6. C) Itch deficient mice develop high spontaneous IgG, which is rescued in mice lacking T cells, supporting the idea that T-B interactions are required for high IgG. Whether Itch activity to prevent excess IgG occurs in germinal centers, extrafollicular interactions, within T cells or B cells is unknown. Speculations can be made by considering the roles of Itch that have been described in B cells and other cell types. Itch ubiquitylation of the signaling component of the BCR alters signaling, and this may dampen spontaneous IgG. Itch regulation of antigen presentation, CXCR4, or Fas would impact germinal center B cell proliferation, survival and IgG production. Itch might regulate spontaneous Tfh by a distinct mechanism from virus-induced Tfh. D) How Itch limits autoantibody is unknown. Determining how Itch limits autoantibody has high clinical relevance for autoimmune patients, including those with Itch deficiency.