Peripheral tolerance occurs after intraocular administration of Ag and is d
ependent on an increase in splenic NKT cells. New data here show that macro
phage inflammatory protein-2 (MIP-2) is selectively up-regulated in toleran
ce-conferring APCs and serves to recruit NKT cells to the splenic marginal
zone, where they form clusters with APCs and T cells. In the absence of the
high-affinity receptor for MIP-2 las in CXCR2-deficient mice) or in the pr
esence of a blocking Ab to MIP-2, peripheral tolerance is prevented, and Ag
-specific T regulatory cells are not generated. Understanding the regulatio
n of lymphocyte traffic during tolerance induction may lead to novel therap
ies for autoimmunity, graft acceptance, and tumor rejection.