MeCP2 Reinforces STAT3 Signaling and the Generation of Effector CD4+ T Cells by Promoting miR-124-Mediated Suppression of SOCS5

Methyl CpG binding protein 2 (MeCP2) is an X-linked, multifunctional epigenetic regulator that is best known for its role in the neurological disorder Rett syndrome; however, it is also linked to multiple autoimmune disorders. We examined a potential role for MeCP2 in regulating the responses of CD4(+) T cells to stimulation with antigen. MeCP2 was indispensable for the differentiation of nave CD4(+) T cells into T helper type 1 (T(H)1) and T(H)17 cells and for T(H)1- or T(H)17-mediated pathologies in vitro and in vivo. Loss of MeCP2 in CD4(+) T cells impaired the expression of the microRNA (miR) miR-124 and consequently relieved miR-124-mediated repression of the translation of suppressor of cytokine signaling 5 (Socs5) mRNA. The resulting accumulation of SOCS5 inhibited the cytokine-dependent activation of signal transducer and activator of transcription 1 (STAT1) and STAT3, which are necessary for the differentiation of T(H)1 and T(H)17 cells, respectively. Upon silencing of MeCP2, primary neurons and astrocytes also failed to respond properly to STAT3-dependent signaling stimulated by neurotrophic factors. Together, these findings suggest that the regulation of STAT3 signaling may represent a common etiology underpinning the roles of MeCP2 in both the nervous and immune systems.