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 naïve CD4⁺ T cells into T helper type 1 (T_H1) and T_H17 cells and for T_H1- or T_H17-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_H1 and T_H17 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.