Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is mediated by myelin-speci fic CD4(+) T cells secreting Th1 cytokines, while recovery from disease is associated with expression of Th2 cytokines. Investigations into the role o f individual cytokines in disease induction have yielded contradictory resu lts. Here we used animals with targeted deletion of the STAT4 or STAT6 gene s to determine the role of these signaling molecules in EAR The STAT4 pathw ay controls the differentiation of cells into a Th1 phenotype, while the ST AT6 pathway controls the differentiation of cells into a Th2 phenotype. We found that mice deficient in STAT4 are resistant to the induction of EAE, x vith minimal inflammatory infiltrates in the central nervous system. In con trast, STAT6-deficient mice, which have a predominantly Th1 phenotype, expe rience a more severe clinical course of EAE as compared with wild-type or S TAT4 knockout mice. In addition, adoptive transfer studies confirm the regu latory functions of a Th2 environment in vivo. These novel data indicate th at STAT4 and STAT6 genes play a critical role in regulating the autoimmune response in EAE.