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

Abstract

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. We showed that MeCP2 was indispensable for the differentiation of naïve CD4+ T cells into T helper type 1 (TH1) and TH17 cells and for TH1- or TH17-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 protein led to inhibition of the cytokine-dependent activation of signal transducer and activator of transcription 1 (STAT1) and STAT3, which are necessary for the differentiation of TH1 and TH17 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.

MeCP2 enforces Foxp3 expression to promote regulatory T cells’ resilience to inflammation

“…This was a strong indication that the loss of MeCP2 in other T-cell subsets might compensate for Treg dysfunction and prevent the onset of overt autoimmunity. Indeed, we have examined the function of MeCP2 in effector T-cell lineages and found that MeCP2-deficient effector CD4 T cells are severely impaired in their production of inflammatory Th1 and Th17 cytokines (55). Nonetheless, it is clear that T-cell immunity is not normal in these animals.…”

Roles of Methyl-CpG Binding Protein 2 in Immune Function

“…Evidence for this from both our lab and others has been accumulating in recent years (Cronk et al, 2015a;Cronk et al, 2015b;Derecki et al, 2012;Horiuchi et al, 2016;Jiang et al, 2014;Jin et al, 2015;Li et al, 2014;Maezawa and Jin, 2010;O'Driscoll et al, 2013b;O'Driscoll et al, 2015). …”

“…It was previously shown by ourselves and others that MeCP2 plays an important role in immune cells, including T cells (Balmer et al, 2002;Jiang et al, 2014;Li et al, 2014;Yang et al, 2012) and myeloid cells (Cronk et al, 2015a;Derecki et al, 2012;Jin et al, 2015;Maezawa and Jin, 2010;O'Driscoll et al, 2013b;O'Driscoll et al, 2015), and thus it was hypothesized that chronic infections seen in MeCP2 (Yang et al, 2012). This defect in IFNγ production was hypothesized to account for the chronic infections seen in MeCP2 duplication syndrome (Yang et al, 2012 More recently, defects in antibody production have been implicated in MeCP2 overexpression.…”

“…Although researchers have analyzed different cell populations, stimuli, and experimental models, all have found in common that response to inflammatory stimuli is affected when MeCP2 function is altered (Cronk et al, 2015a;Jiang et al, 2014;Li et al, 2014;O'Driscoll et al, 2013b;O'Driscoll et al, 2015;Yang et al, 2012). With this in mind, understanding how MeCP2 will regulate an immune …”

“…However, studies using mice that specifically overexpress only MeCP2, and not IRAK1, have demonstrated that MeCP2 significantly influences immune function on its own (Koelsch et al, 2013;Yang et al, 2012 (Koelsch et al, 2013;Yang et al, 2012), but also MeCP2 loss-of-function / Rett syndrome (Cronk et al, 2015a;Cronk et al, 2015b;Derecki et al, 2012;Horiuchi et al, 2016;Jiang et al, 2014;Jin et al, 2015;Li et al, 2014;Maezawa and Jin, 2010;O'Driscoll et al, 2013b;O'Driscoll et al, 2015), and potentially even other immunologic disorders outside of either Rett or MeCP2 duplication (Carmona et al, 2013;Cobb et al, 2010;Han et al, 2013;Kaufman et al, 2013;Koelsch et al, 2013;Sawalha et al, 2008;Webb et al, 2009). …”