Intrafollicular location of marginal zone/CD1dhi B cells is associated with autoimmune pathology in a mouse model of lupus

Marginal zone ( MZ) B cells contain a large number of autoreactive clones and the expansion of this compartment has been associated with autoimmunity. MZ B cells also efficiently transport blood- borne antigen to the follicles where they activate T cells and differentiate into plasma cells. Using the B6. NZM2410. Sle1. Sle2. Sle3 ( B6. TC) model of lupus, we show that the IgM_ CD1d hi/ MZ B- cell compartment is expanded, and a large number of them reside inside the follicles. Contrary to the peripheral B- cell subset distribution and their activation status, the intrafollicular location of B6. TC IgM_ CD1d hi/ MZ B cells depends on both bone marrow- and stromal- derived factors. Among the factors responsible for this intrafollicular location, we have identified an increased response to CXCL13 by B6. TC MZ B cells and a decreased expression of VCAM- 1 on stromal cells in the B6. TC MZ. However, the reduced number of MZ macrophages observed in B6. TC MZs was independent of the IgM_ CD1d hi/ B- cell location. B7- 2 but not B7- 1 deficiency restored IgM_ CD1d hi/ MZ B- cell follicular exclusion in B6. TC mice, and it correlated with tolerance to dsDNA and a significant reduction of autoimmune pathology. These results suggest that follicular exclusion of IgM_ CD1d hi/ MZ B cells is an important B- cell tolerance mechanism, and that B7- 2 signaling is involved in breaching this tolerance checkpoint.