Anti-TBX21 monoclonal antibody, clone FQS0413

Foxp3+ regulatory T (Treg) cells modulate the functions of multiple immune cell types, and loss of Treg cells causes lethal, CD4+ T-cell-dependent multiorgan autoimmune disease in both mice and humans. However, how different effector T-cell subets contribute to the severe autoimmunity observed in the absence of Treg cells remains controversial. We found that although expanded populations of Th1, Th2, and Th17 cells can be detected in scurfy (sf) mice, Th1 cells predominate. Moreover, using a genetic approach, we found that sf mice with deficiencies in type-1 immunity (sf X Ifngr1-/-, sf X Tbx21-/-, and sf X Ifngr1-/-/Tbx21-/-) have an extended lifespan that is associated with altered cytokine production and attenuated cutaneous and hepatic inflammation. By contrast, sf mice deficient in type-2 immune responses (sf X Stat6-/-) display a significantly reduced lifespan with increased hepatic inflammation, but decreased dermatitis. These data indicate that Th1 cells and their associated cytokines drive early immunopathology in Foxp3-deficient sf mice, highlighting the essential role of Treg cells in restraining Th1-cell-mediated autoimmunity.

Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for T(H)17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed T(H)17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2(-/-) mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2(-/-) mice. In addition, Mbd2(-/-) mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE. (C) 2014 Elsevier Ltd. All rights reserved.