Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4 + T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

Lymphocytes must proliferate and differentiate in response to low concentrations of a vast array of antigens. The requirements of broad specificity and sensitivity conflict because the former is met by low-affinity antigen receptors, which precludes achieving the latter with high-affinity receptors. Coligation of the membrane protein CD19 with the antigen receptor of B lymphocytes decreased the threshold for antigen receptor-dependent stimulation by two orders of magnitude. B lymphocytes proliferated when approximately 100 antigen receptors per cell, 0.03 percent of the total, were coligated with CD19. The B cell resolves its dilemma by having an accessory protein that enables activation when few antigen receptors are occupied.

Antigen receptors on B and T lymphocytes transduce signals by activating nonreceptor protein tyrosine kinases (PTKs). A family of receptor PTKs contains kinase insert regions with the sequence tyrosine-X-X-methionine (where X is any amino acid) that when phosphorylated mediate the binding and activation of phosphatidylinositol 3-kinase (PI 3-kinase). The CD19 membrane protein of B cells enhances activation through membrane immunoglobulin M (mIgM) and was found to contain a functional analog of the kinase insert region. Ligation of mIgM induced phosphorylation of CD19 and association with PI 3-kinase. Thus, CD19 serves as a surrogate kinase insert region for mIgM by providing the means for PI 3-kinase activation by nonreceptor PTKs.